Composite shaped bodies and methods for their production and use

ABSTRACT

Shaped, composite bodies are provided. One portion of the shaped bodies comprises an RPR-derived porous inorganic material, preferably a calcium phosphate. Another portion of the composite bodies is a different solid material, preferably metal, glass, ceramic or polymeric. The shaped bodies are especially suitable for orthopaedic and other surgical use.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 09/373,796, the contents of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to the preparation of composite shapedbodies, especially those having at least a portion comprising a calciumphosphate-containing material. This invention also relates to methodsfor preparing the bodies and to methods for use thereof. In accordancewith certain embodiments of this invention, shaped bodies are providedwhich are at once, possessed of two or more portions having differentproperties. In accordance with other preferred embodiments, at least oneportion of the composite is highly porous and uniform in composition.The shaped bodies can be produce in a wide range of geometricconfigurations through novel, low temperature techniques. The shapedbodies of the invention can have portions which are highly and uniformlyporous while being self-supporting. They can be strengthened furtherusing a variety of techniques, thereby forming porous compositestructures. Such composite structures are useful as cell growthscaffolds, bone grafting materials, drug delivery vehicles, biologicalseparation/purification media, catalysis and other supports and in awide range of other uses. One of the most preferred uses for thecomposite structures of this invention is in the field of orthopaedic,restorative and reconstructive surgery. Thus, the present inventionprovides shaped bodies having highly suitable combinations of propertieswhich make those bodies extraordinarily useful for bone replacement,spinal repair; reconstructive, cosmetic and other surgeries.

BACKGROUND OF THE INVENTION

[0003] There has been a continuing need for improved methods for thepreparation of mineral compositions, especially calciumphosphate-containing minerals. This long-felt need is reflected in partby the great amount of research found in the pertinent literature. Whilesuch interest and need stems from a number of industrial interests, thedesire to provide materials which closely mimic mammalian bone for usein repair and replacement of such bone has been a major motivatingforce. Such minerals are principally calcium phosphate apatites as foundin teeth and bones. For example, type-B carbonated hydroxyapatite[Ca5(PO4)3-x(CO3)x(OH)] is the principal mineral phase found in thebody, with variations in protein and organic content determining theultimate composition, crystal size, morphology, and structure of thebody portions formed therefrom.

[0004] Calcium phosphate ceramics have been fabricated and implanted inmammals in various forms including, but not limited to, shaped bodiesand cements. Different stoichiometric compositions such ashydroxyapatite (HAp), tricalcium phosphate (TCP), tetracalcium phosphate(TTCP), and other calcium phosphate salts and minerals, have all beenemployed to this end in an attempt to match the adaptability,biocompatibility, structure, and strength of natural bone. The role ofpore size and porosity in promoting revascularization, healing, andremodeling of bone is now recognized as a critical property for bonereplacement materials. Despite tremendous efforts directed to thepreparation of porous calcium phosphate materials for such uses,significant shortcomings still remain. This invention overcomes thoseshortcomings and describes porous calcium phosphate and a wide varietyof other inorganic materials which, in the case of calcium phosphates,closely resemble bone, and methods for the fabrication of such materialsas shaped bodies for biological, chemical, industrial, and many otherapplications.

[0005] Early ceramic biomaterials exhibited problems derived fromchemical and processing shortcomings that limited stoichiometriccontrol, crystal morphology, surface properties, and, ultimately,reactivity in the body. Intensive milling and comminution of naturalminerals of varying composition was required, followed by powderblending and ceramic processing at high temperatures to synthesize newphases for use in vivo.

[0006] A number of patents have issued which relate to ceramicbiomaterials and are incorporated herein by reference. Among these areU.S. Pat. No. 4,880,610, B. R. Constantz, “In situ calcium phosphateminerals—method and composition;” U.S. Pat. No. 5,047,031, B. R.Constantz, “In situ calcium phosphate minerals method;” U.S. Pat. No.5,129,905, B. R. Constantz, “Method for in situ prepared calciumphosphate minerals;” U.S. Pat. No. 4,149,893, H. Aoki, et al,“Orthopaedic and dental implant ceramic composition and process forpreparing same;” U.S. Pat. No. 4,612,053, W. E. Brown, et al,“Combinations of sparingly soluble calcium phosphates in slurries andpastes as mineralizers and cements;” U.S. Pat. No. 4,673,355, E. T.Farris, et al, “Solid calcium phosphate materials;” U.S. Pat. No.4,849,193, J. W. Palmer, et al., “Process of preparing hydroxyapatite;”U.S. Pat. No. 4,897,250, M. Sumita, “Process for producing calciumphosphate;” U.S. Pat. No. 5,322,675, Y. Hakamatsuka, “Method ofpreparing calcium phosphate;” U.S. Pat. No. 5,338,356, M. Hirano, et al“Calcium phosphate granular cement and method for producing same;” U.S.Pat. No. 5,427,754, F. Nagata, et al., “Method for production ofplatelike hydroxyapatite;” U.S. Pat. No. 5,496,399, I. C. Ison, et al.,“Storage stable calcium phosphate cements;” U.S. Pat. No. 5,522,893, L.C. Chow. et al., “Calcium phosphate hydroxyapatite precursor and methodsfor making and using same;” U.S. Pat. No. 5,545,254, L. C. Chow, et al.,“Calcium phosphate hydroxyapatite precursor and methods for making andusing same;” U.S. Pat. No. 3,679,360, B. Rubin, et al., “Process for thepreparation of brushite crystals;” U.S. Pat. No. 5,525,148, L. C. Chow,et al., “Self-setting calcium phosphate cements and methods forpreparing and using them;” U.S. Pat. No. 5,034,352, J. Vit, et al.,“Calcium phosphate materials;” and U.S. Pat. No. 5,409,982, A. Imura, etal “Tetracalcium phosphate-based materials and process for theirpreparation.”

[0007] Several patents describe the preparation of porous inorganic orceramic structures using polymeric foams impregnated with a slurry ofpreformed ceramic particles. These are incorporated herein by reference:U.S. Pat. No. 3,833,386, L. L. Wood, et al, “Method of preparing porousceramic structures by firing a polyurethane foam that is impregnatedwith inorganic material;” U.S. Pat. No. 3,877,973, F. E. G. Ravault,“Treatment of permeable materials;” U.S. Pat. No. 3,907,579, F. E. G.Ravault, “Manufacture of porous ceramic materials;” and U.S. Pat. No.4,004,933, F. E. G. Ravault, “Production of porous ceramic materials.”However, none of aforementioned art specifically describes thepreparation of porous metal or calcium phosphates and none employs themethods of this invention.

[0008] The prior art also describes the use of solutionimpregnated-polymeric foams to produce porous ceramic articles and theseare incorporated herein by reference: U.S. Pat. No. 3,090,094, K.Schwartzwalder, et al, “Method of making porous ceramic articles;” U.S.Pat. No. 4,328,034 C. N. Ferguson, “Foam Composition and Process;” U.S.Pat. No. 4,859,383, M. E. Dillon, “Process of Producing a CompositeMacrostructure of Organic and Inorganic Materials;” U.S. Pat. No.4,983,573, J. D. Bolt, et al, “Process for making 90° K superconductorsby impregnating cellulosic article with precursor solution;” U.S. Pat.No. 5,219,829, G. Bauer, et al, “Process and apparatus for thepreparation of pulverulent metal oxides for ceramic compositions;” GB2,260,538, P. Gant, “Porous ceramics;” U.S. Pat. No. 5,296,261, J.Bouet, et al, “Method of manufacturing a sponge-type support for anelectrode in an electrochemical cell;” U.S. Pat. No. 5,338,334, Y. S.Zhen, et al, “Process for preparing submicron/nanosize ceramic powdersfrom precursors incorporated within a polymeric foam;” and S. J. Powelland J. R. G. Evans, “The structure of ceramic foams prepared frompolyurethane-ceramic suspensions,” Materials & Manufacturing Processes,10(4):757 (1995). The focus of this art is directed to the preparationof either metal or metal oxide foams and/or particles. None of thedisclosures of these aforementioned references mentions in situ solidphase formation via redox precipitation reaction from homogeneoussolution as a formative method.

[0009] The prior art also discloses certain methods for fabricating,inorganic shaped bodies using natural, organic objects. Thesefabrication methods, however, are not without drawbacks which includecracking upon drying the green body and/or upon firing. To alleviatethese problems, the fabrication processes typically involve controlledtemperature and pressure conditions to achieve the desired end product.In addition, prior fabrication methods may include the additional stepsof extensive material preparation to achieve proper purity, particlesize distribution and orientation, intermediate drying and radiationsteps, and sintering at temperatures above the range desired foremployment in the present invention. For example, U.S. Pat. No.5,298,205 issued to Hayes et. al. entitled “Ceramic Filter Process”,incorporated herein by reference, discloses a method of fabricating aporous ceramic body from an organic sponge saturated in an aqueousslurry comprised of gluten and particulate ceramic material fired at atemperature range from 1,100° to 1,300° C. Hayes teaches that thesaturated sponge must be dehydrated prior to firing via microwaveradiation, and includes a pre-soak heating step, and a hot pressingstep.

[0010] While improvements have been made in materials synthesis andceramic processing technology leading to porous ceramics and ceramicbiomaterials, improved preparative methods, and the final products thesemethods yield, are still greatly desired. Generation of controlledporosity in ceramic biomaterials generally, and in calcium phosphatematerials in particular, is crucial to the effective in vitro and invivo use of these synthetic materials for regenerating human cells andtissues. This invention provides both novel, porous calcium phosphatematerials and methods for preparing them. Methods relating to calciumphosphate-containing biomaterials, which exhibit improved biologicalproperties, are also greatly desired despite the great efforts of othersto achieve such improvements.

[0011] In particular, this invention provides such novel, porous calciumphosphate and other materials in composite forms, especially in shapedbodies. Thus, the benefits of these novel materials are now enhancedthrough combining into such shaped bodies areas of the novel materialsalong with areas or portions comprising other materials.

[0012] Accordingly, it is a principal object of this invention toprovide improved inorganic, porous, shaped bodies, especially thoseformed of calcium phosphate.

[0013] Such shaped bodies having a plurality of portions, one of whichcomprises the novel, inorganic, porous materials of this invention arealso provide by this invention.

[0014] Another object is to provide shaped bodies for surgical,orthopaedic, reconstructive and restorative uses.

[0015] A further object of the invention is to provide methods forforming such materials with improved yields, lower processingtemperatures, greater compositional flexibility, and better control ofporosity.

[0016] Yet another object provides materials with micro-, meso-, andmacroporosity, as well as the ability to generate shaped porous solidshaving improved uniformity, biological activity, catalytic activity, andother properties.

[0017] Another object is to provide porous materials which are useful inthe repair and/or replacement of bone in orthopaedic and dentalprocedures.

[0018] An additional object is to prepare a multiplicity of high purity,complex shaped objects, formed at temperatures below those commonly usedin traditional firing methods.

[0019] Further objects will become apparent from a review of the presentspecification.

SUMMARY OF THE INVENTION

[0020] The present invention is directed to new inorganic bodies,especially controllably porous bodies, which can be formed intovirtually any geometric shape. The novel preparative methods of theinvention utilize redox precipitation chemistry or aqueous solutionchemistry, which is described in pending U.S. patent application Ser.No. 08/784,439 assigned to the present assignee and, incorporated hereinby reference. In accordance with certain preferred embodiments, theredox precipitation chemistry is utilized in conjunction with asacrificial, porous cellular support, such as an organic foam or sponge,to produce a porous inorganic product which faithfully replicates boththe bulk geometric form as well as the macro-, meso-, and microstructureof the precursor organic support. The aqueous solution, because of itsunique chemistry, has a high solids equivalent, yet can essentially beimbibed fully into and infiltrate thoroughly the microstructure of thesacrificial organic precursor material. This extent of infiltrationallows the structural details and intricacies of the precursor organicfoam materials to be reproduced to a degree heretofore unattainable.This great improvement can result in porous minorganic materials havingnovel microstructural features and sufficient robustness to be handledas coherent bodies of highly porous solid.

[0021] The invention also gives rise to porous inorganic materialshaving improved compositional homogeneity, multiphasic character, and/ormodified crystal structures at temperatures far lower than thoserequired in conventional formation methods. In addition, the inventionalso gives rise to porous inorganic composites comprising mineralscaffolds strengthened and/or reinforced with polymers, especiallyfilm-forming polymers, such as gelatin.

[0022] The present invention is also directed to composite shaped bodiescomprising two or more portions. One of the portions is the reactionproduct of a metal cation and an oxidizing agent together with aprecursor anion oxidizable by the oxidizing agent. The reaction is onewhich gives rise to at least on gaseous product. Another portion of thecomposite shaped bodies of the invention is another solid. Such solidmay be any of a wide range of materials such as metal, especiallytitanium, stainless steel and other surgical metals, ceramic, glass,polymer or other generally hard material. The composite shaped bodiesare ideally suited for surgical use, especially in orthopaedics and inreconstructive and restorative surgery. The porous materials forming oneportion of the composite bodies of the invention are high compatiblewith such surgical use and can give rise to osteogenesis orosteostimulation in some cases. This is especially true of calciumphosphate materials.

[0023] The new paradigm created by this invention is facilitated by adefinition of terms used in the description of embodiments. The generalmethod starts with infiltrant solutions produced from raw materialsdescribed herein as salts, aqueous solutions of salts, stable hydrosolsor other stable dispersions, and/or inorganic acids. The sacrificial,porous organic templates used in some embodiments may be organic foams,cellular solids and the like, especially open-cell hydrophilic materialwhich can imbibe the aqueous infiltrant solutions. Both the precursororganic templates, as well as the inorganic replicas produced inaccordance within this invention, display a porosity range of at least 3orders of magnitude. This range of porosity can be described as macro-,meso- and microporous. Within the scope of this invention, macroporosityis defined as having a pore diameter greater than or equal to 100microns, mesoporosity is defined as having a pore diameter less than 100microns but greater than or equal to 10 microns, and microporosity isdefined as having a pore diameter less than 10 microns.

[0024] In addition to the controlled macro-, meso- and microporosityranges, inorganic shaped bodies have been fabricated possessing porevolumes of at least about 30%. In preferred embodiments, pore volumes ofover 50% have been attained and pore volumes in excess of 70% or 80% aremore preferred. Materials having macro-, meso- and microporositytogether with pore volumes of at least about 90% can be made as canthose having pore volumes over 92% and even 94%. In some cases, porevolumes approaching 95% have been ascertained in products which,nevertheless, retain their structural integrity and pore structure.

[0025] The phases produced by the methods of this invention [RedoxPrecipitation Reaction (RPR) and Hydrothermal PROCESSING (HYPR)]initially are intermediate or precursor minerals, which can be easilyconverted to a myriad of pure and multiphasic minerals of previouslyknown and, in some cases, heretofore undefined stoichiometry, generallyvia a thermal treatment under modest firing regimens compared to knownand practiced conventional art.

[0026] In accordance with certain embodiments of the present invention,methods are provided for the restoration of bony tissue. In this regard,an area of bony tissue requiring repair as a result of disease, injury,desired reconfiguration and the like, is identified and preferablymeasured. A block of porous calcium phosphate material can be made tofit the dimensions of the missing or damaged bony tissue and implantedin place by itself or in conjunction with biocompatible bonding materialcompositions such as those disclosed in U.S. Pat. No. 5,681,872 issuedin the name of E. M. Erbe on Oct. 28, 1997 and incorporated herein byreference. The calcium phosphate material can also be used as a “sleeve”or form for other implants, as a containment vessel for the bonegrafting material which is introduced into the sleeve for the repair,and in many other contexts.

[0027] A major advantage of the restoration is that afterpolymerization, it has a significant, inherent strength, such thatrestoration of load-bearing bony sites can be achieved. Whileimmobilization of the effected part will likely still be required, thepresent invention permits the restoration of many additional bony areasthan has been achievable heretofore. Further, since the porous calciumphosphate scaffolding material of the present invention is biocompatibleand, indeed, bioactive, osteogenesis can occur. This leads to boneinfiltration and replacement of the calcium phosphate matrix withautologous bone tissue.

[0028] The calcium phosphate scaffolding material of the presentinvention may also be made into shaped bodies for a variety of uses.Thus, orthopaedic appliances such as joints, rods, pins, or screws fororthopaedic surgery, plates, sheets, and a number of other shapes may beformed from the material in and of itself or used in conjunction withconventional appliances that are known in the art. Such hardenedcompositions can be bioactive and can be used, preferably in conjunctionwith hardenable compositions in accordance with the present invention inthe form of gels, pastes, or fluids, in surgical techniques. Thus, ascrew or pin can be inserted into a broken bone in the same way thatmetal screws and pins are currently inserted, using conventional bonecements or restoratives in accordance with the present invention orotherwise. The bioactivity of the present hardenable materials give riseto osteogenesis, with beneficial medical or surgical results.

[0029] The methods of the invention are energy efficient, beingperformed at relatively low temperature; have high yields; and areamenable to careful control of product shape, macro- and microstructure,porosity, and chemical purity. Employment as bioactive ceramics is aprincipal, anticipated use for the materials of the invention, withimproved properties being extant. Other uses of the porous minerals andprocesses for making the same are also within the spirit of theinvention.

[0030] The present invention also provides exceptionally fine, uniformpowders of inorganic materials. Such powders have uniform morphology,uniform composition and narrow size distribution. They may be attainedthrough the comminution of shaped bodies in accordance with theinvention and have wide utility in chemistry, industry, medicine andotherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031]FIG. 1 depicts an aggregated physical structure of an RPRgenerated, multiphasic β-tricalcium phosphate (β-TCP)+type-B carbonatedapatite (c-HAp) [β-Ca3(PO4)2+Ca5(PO₄)3-x(CO3)x(OH)] prepared inaccordance with one embodiment of this invention. The entireagglomerated particle is approximately 10 μm, and the individualcrystallites are typically less than about 1 μm and relatively uniformin particle size and shape.

[0032]FIG. 2 represents assembled monetite, CaHPO₄ particles formed froma hydrothermal precipitation in accordance with certain methods taughtby this invention. The entire particle assemblage is typically about 30μm and is comprised of relatively uniformly rectangular cubes andplate-like crystallites of various sizes and aspect ratios.

[0033]FIG. 3 illustrates a water purification disk that is comprised ofthe porous inorganic material of the present invention and is containedwithin an exterior housing for filtration or separation purposes.

[0034]FIG. 4 illustrates shaped bodies of porous inorganic material ofthe present invention used as a catalyst support within a hot gasreactor or diffusor.

[0035]FIG. 5 illustrates shaped bodies of porous calcium phosphatematerial of the present invention implanted at several sites within ahuman femur for cell seeding, drug delivery, protein adsorption, orgrowth factor scaffolding purposes.

[0036] FIGS. 6A and FIG. 6B illustrate one embodiment of porous calciumphosphate scaffolding material of the present invention used as anaccommodating sleeve in which a tooth is screwed, bonded, cemented,pinned, anchored, or otherwise attached in place.

[0037]FIGS. 7 and 7A illustrate another embodiment of the porous calciumphosphate scaffolding material of the present invention used as acranio-maxillofacial, zygomatic reconstruction and mandibular implant.

[0038]FIGS. 8A and 8B illustrate one embodiment of the porous calciumphosphate scaffolding material of the present invention shaped into ablock form and used as a tibial plateau reconstruction that is screwed,bonded, cemented, pinned, anchored, or otherwise attached in place.

[0039]FIG. 9 illustrates an embodiment of the porous calcium phosphatescaffolding material of the present invention shaped into a block orsleeve form and used for the repair or replacement of bulk defects inmetaphyseal bone, oncology defects or screw augmentation.

[0040]FIGS. 10A and 10B illustrate an embodiment of the porous calciumphosphate scaffolding material of the present invention shaped into asleeve form and used for impaction grafting to accommodate an artificialimplant said sleeve form being screwed, bonded, pinned or otherwiseattached in place.

[0041]FIG. 11 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous calcium phosphate material fired at 500° C. in accordance withone embodiment of this invention. The sample consists of a biphasicmixture of whitlockite Ca₃(PO₄)₂(PDF 09-0169) and hydroxyapatiteCa₅(PO₄)₃(OH) (PDF 09-0432).

[0042]FIG. 12 is a 50×magnification scanning electron micrograph of avirgin cellulose sponge material used to prepare several of theembodiments of this invention.

[0043]FIG. 13 is a 100×magnification scanning electron micrograph ofporous calcium phosphate material fired at 500° C. in accordance withone embodiment of this invention.

[0044]FIG. 14 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous calcium phosphate material fired at 1100° C. in accordancewith one embodiment of this invention. The sample consists ofwhitlockite Ca₃(PO₄)₂ (PDF 09-0169).

[0045]FIG. 15 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous calcium phosphate material fired at 1350° C. in accordancewith one embodiment of this invention. The sample consists ofwhitlockite Ca₃(PO₄)₂ (PDF 09-0169).

[0046]FIG. 16 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous calcium phosphate material fired at 800° C. in accordance withone embodiment of this invention. The sample consists of calciumpyrophosphate, Ca₂P₂O₇ (PDF 33-0297).

[0047]FIG. 17 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous zinc phosphate material fired at 500° C. in accordance withone embodiment of this invention. The sample consists of zinc phosphate,Zn₃(PO₄)₂ (PDF 30-1490).

[0048]FIG. 18 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous neodymium phosphate material fired at 500° C. in accordancewith one embodiment of this invention. The sample consists of neodymiumphosphate, NdPO₄ (PDF 25-1065).

[0049]FIG. 19 is an X-ray diffraction (XRD) plot of a pulverized sampleof porous aluminum phosphate material fired at 500° C. in accordancewith one embodiment of this invention. The sample consists of aluminumphosphate, AIPO₄ (PDF 11-0500).

[0050]FIG. 20 is a 23×magnification scanning electron micrographdepicting the macro- and meso-porosity of porous calcium phosphatematerial fired at 500° C. and reinforced with gelatin in accordance withone embodiment of this invention.

[0051]FIG. 21 is a 25×magnification scanning electron micrograph ofsheep trabecular bone for comparative purposes.

[0052]FIG. 22 is a 2000×magnification scanning electron micrograph ofthe air-dried gelatin treated inorganic sponge depicted in FIG. 20 whichexhibits meso- and microporosity in the calcium phosphate matrix. FIGS.20 and 22, together, demonstrate the presence of macro-, meso-, andmicroporosity simultaneously in a highly porous product.

[0053]FIG. 23 is an X-ray diffraction (XRD) plot of a pulverized sampleof the ash remaining after firing at 500° C. of the virgin cellulosesponge starting material used to prepare several of the embodiments ofthis invention. The ash sample consists of a biphasic mixture ofmagnesium oxide, MgO (major) (PDF 45-0946) and sodium chloride, NaCl(minor) (PDF 05-0628).

[0054]FIG. 24 is a 20×magnification scanning electron micrograph of avirgin cellulose sponge starting material, expanded from its compressedstate, used to prepare several of the embodiments of this invention.

[0055]FIG. 25 is a 20×magnification scanning electron micrograph ofporous calcium phosphate material fired at 800° C. and reinforced withgelatin in accordance with one embodiment of this invention.

[0056]FIG. 26 depicts a calcium phosphate porous body, produced inaccordance with one embodiment of this invention partially wicked withblood.

[0057]FIG. 27 shows a cylinder of calcium phosphate prepared inaccordance with one embodiment of this invention, implanted into themetaphyseal bone of a canine.

[0058]FIG. 28 is an X-ray diffraction plot of a pulverized sample of acation substituted hydroxyapatite material processed in accordance withthe methods described in this invention.

[0059]FIG. 29 depicts a synthetic cortical vertebral ring insertedbetween a pair of vertebrae in a spine. The injection of hardenablematerial, such as bone cement, into a port in the cortical ring isshown.

[0060]FIG. 30 is a lateral view of a synthetic cortico-cancellousvertebral ring or interbody fusion device. The composite nature of thedevice is shown to comprise first and second portions comprisingdifferent materials.

[0061]FIGS. 31 through 34 all depict spinal surgical applications withvertebrae depicted in phantom, 220.

[0062]FIG. 31 shows one embodiment of a synthetic cortical bone dowel inplace. The dowel has a plurality of ports, some of which are shown 224.

[0063]FIG. 32 depicts another bone dowel for spinal fusion.

[0064]FIG. 33 shows a synthetic cortical interbody vertebral defectfilling form.

[0065]FIG. 34 shows a cross section of a spinal fusion employing ashaped body of the invention potted in hardenable material.

[0066]FIGS. 35a, 35 b and 35 c depict synthetic cortical vertebralspacers or interbody devices. FIGS. 35b and 35 c are in the shape ofrings.

[0067]FIGS. 36a through c depict synthetic cortical bone dowels orinterbody devices.

[0068]FIG. 37 is another form of cortical spacer.

[0069]FIG. 38 is of a synthetic cancellous bone dowel.

[0070]FIG. 39 is a synthetic cortical vertebral interbody device.

[0071]FIGS. 40a, and 40 c are of synthetic cortico-cancellous defectfilling forms for bone restoration. FIG. 40b shows a cancellous defectfilling form.

[0072]FIGS. 41a and 41 b are drawn to bone dowels.

[0073]FIG. 42 is a synthetic cortical ring

[0074]FIG. 43 is a cortical rod for orthopaedic restoration

[0075]FIG. 44 is a synthetic cortico-cancellous “tri-cortical” device

[0076]FIG. 45 depicts a cortico-cancellous “crouton” for orthopaedicsurgery.

[0077]FIG. 46 is a “match stick” orthopaedic surgical splint.

[0078]FIG. 47a and 47 b are cortical struts for surgical use.

[0079]FIGS. 48, 49, 50 a and 50 b are cortical rings.

[0080]FIG. 51 depicts an artificial femur head for reconstructivesurgery.

[0081]FIG. 52 is an artificial bone portion

[0082]FIG. 53 is a strut or tube for reconstruction.

[0083]FIG. 54 is an acetabular/pelvic form for orthopaedicreconstruction.

[0084]FIG. 55a and b depict insertion of a femoral hip dowel into afemur.

[0085]FIGS. 56a through d are different forms of dowels for orthopaedicuse.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0086] In accordance with this invention, composite shaped bodies areprovided which are useful, e.g. in orthopaedic and other surgery. Thebodies have a first portion which is a solid and which is attached to,adhered to, coformed with or in contact with a second portion. Thesecond portion is reaction product of a blend comprising at least onemetal cation at least one oxidizing agent; and at least one precursoranion oxidizable by said oxidizing agent to form an oxoanion. Thereaction gives rise to at least one gaseous product and is generally ofthe type of reaction known as oxidation-reduction reactions. Thisresults in what is termed an RPR-derived material. The resultingcomposite shaped bodies may be formed into nearly any shape, includingshapes usefuil in orthopaedic and other surgery, especially when theRPR-derived material is a calcium phosphate.

[0087] The RPR-derived material is usually arrived at in two stages.Thus, a precursor mineral is formed from an immediateoxidation-reduction reaction, and then that material is consolidated ortransformed into a final calcium phosphate or other material. Inaccordance with the present invention, methods are provided forpreparing shapes comprising an intermediate precursor mineral of atleast one metal cation and at least one oxoanion. These methods comprisepreparing an aqueous solution of the metal cation and at least oneoxidizing agent. The solution is augmented with at least one solubleprecursor anion oxidizable by said oxidizing agent to give rise to theprecipitant oxoanion. The oxidation-reduction reaction thus contemplatedis conveniently initiated by heating the solution under conditions oftemperature and pressure effective to give rise to said reaction. Inaccordance with preferred embodiments of the invention, theoxidation-reduction reaction causes at least one gaseous product toevolve and the desired intermediate precursor mineral to precipitatefrom the solution.

[0088] The intermediate precursor mineral thus prepared can either beused “as is” or can be treated in a number of ways. Thus, it may be heattreated in accordance with one or, more paradigms to give rise to apreselected crystal structure or other preselected morphologicalstructures therein. In accordance with preferred embodiments, theoxidizing agent is nitrate ion and the gaseous product is a nitrogenoxide, generically depicted as NO_(x(g)). It is preferred that theprecursor mineral provided by the present methods be substantiallyhomogeneous. It is also preferred for many embodiments that thetemperature reached by the oxidation-reduction reaction not exceed about150° C. unless the reaction is run under hydrothermal conditions or in apressure vessel.

[0089] In accordance with other preferred embodiments, the intermediateprecursor mineral provided by the present invention is a calciumphosphate. It is preferred that such mineral precursor comprise, inmajor proportion, a solid phase which cannot be identified singularlywith any conventional crystalline form of calcium phosphate. At the sametime, the calcium phosphate mineral precursors of the present inventionare substantially homogeneous and do not comprise a physical admixtureof naturally occurring or conventional crystal phases.

[0090] In accordance with preferred embodiments, the low temperatureprocesses of the invention lead to the homogeneous precipitation of highpurity powders from highly concentrated solutions. Subsequent modestheat treatments convert the intermediate material to e.g. novelmonophasic calcium phosphate minerals or novel biphasic β-tricalciumphosphate (β-TCP)+type-B, carbonated apatite (c-HAp)[β-Ca₃(PO₄)₂+Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH)] particulates.

[0091] In other preferred embodiments, calcium phosphate salts areprovided through methods where at least one of the precursor anions is aphosphorus oxoanion, preferably introduced as hypophosphorous acid or asoluble alkali or alkaline-earth hypophosphite salt. For the preparationof such calcium phosphates, it is preferred that the initial pH bemaintained below about 3, and still more preferably below about 1.

[0092] The intermediate precursor minerals prepared in accordance withthe present methods are, themselves, novel and not to be expected fromprior methodologies. Thus, such precursor minerals can be, at once,non-stoichiometric and possessed of uniform morphology.

[0093] It is preferred in connection with some embodiments of thepresent invention that the intermediate precursor minerals produced inaccordance with the present methods be heated, or otherwise treated, tochange their properties. Thus, such materials may be heated totemperatures as low as 300° C. up to about 800° C. to give rise tocertain beneficial transformations. Such heating will remove extraneousmaterials from the mineral precursor, will alter its composition andmorphology in some cases, and can confer upon the mineral a particularand preselected crystalline structure. Such heat treatment can be totemperatures which are considerably less than those used conventionallyin accordance with prior methodologies to produce end product mineralphases. Accordingly, the heat treatments of the present invention donot, necessarily, give rise to the “common” crystalline morphologies ofmonetite, dicalcium or tricalcium phosphate, tetracalcium phosphate,etc., but, rather, they can lead to new and unobvious morphologies whichhave great utility in the practice of the present invention.

[0094] The present invention is directed to the preparation, productionand use of shaped bodies of inorganic materials. It will be appreciatedthat shaped bodies can be elaborated in a number of ways, which shapedbodies comprise an inorganic material. A preferred method for givingrise to the shaped bodies comprising minerals is through the use ofsubject matter disclosed in U.S. Ser. No. 08/784,439 filed Jan. 16,1997, assigned to the assignee of the present invention and incorporatedherein by reference. In accordance with techniques preferred for use inconjunction with the present invention, a blend of materials are formedwhich can react to give rise to the desired mineral, or precursorthereof, at relatively low temperatures and under relatively flexiblereaction conditions. Preferably, the reactive blends thus used includeoxidizing agents and materials which can be oxidized by the oxidizingagent, especially those which can give rise to a phosphorus oxoanion.Many aspects of this chemistry are described hereinafter in the presentspecification. It is to be understood, however, that such reactiveblends react at modest temperatures under modest reaction conditions,usually through the evolution of a nitrogen oxide gas, to give rise tothe minerals desired for preparation or to materials which may betransformed such as through heating or sintering to form such minerals.A principal object of the present invention is to permit such mineralsto be formed in the form of shaped bodies.

[0095] It will be appreciated that preferred compositions of thisinvention exhibit high degrees of porosity. It is also preferred thatthe porosity occur in a wide range of effective pore sizes. In thisregard, persons skilled in the art will appreciate that preferredembodiments of the invention have, at once, macroporosity, mesoporosityand microporosity. Macroporosity is characterized by pore diametersgreater than about 100 μm. Mesoporosity is characterized by porediameters between about 100 and 10 μm, while microporosity occurs whenpores have diameters below about 10 μm. It is preferred that macro-,meso- and microporosity occur simultaneously in products of theinvention. It is not necessary to quantify each type of porosity to ahigh degree. Rather, persons skilled in the art can easily determinewhether a material has each type of porosity through examination, suchas through the preferred method of scanning electron microscopy. Whileit is certainly true that more than one or a few pores within therequisite size range are needed in order to characterize a sample ashaving a substantial degree of that particular form of porosity, nospecific number or percentage is called for. Rather, a qualitativeevaluation by persons skilled in the art shall be used to determinemacro-, meso- and microporosity.

[0096] It is preferred that the overall porosity of materials preparedin accordance with this invention be high. This characteristic ismeasured by pore volume, expressed as a percentage. Zero percent porevolume refers to a fully dense material, which, perforce, has no poresat all. One hundred percent pore volume cannot meaningfully exist sincethe same would refer to “all pores” or air. Persons skilled in the artunderstand the concept of pore volume, however and can easily calculateand apply it. For example, pore volume may be determined in accordancewith W. D. Kingery, Introduction to Ceramics, 1960 p. 416 (Wiley, 1060),who provides a formula for determination of porosity. Expressingporosity as a percentage yields pore volume. The formula is: PoreVolume=(1−f_(p)) 100%, where f_(p) is fraction of theoretical densityachieved.

[0097] Pore volumes in excess of about 30% are easily achieved inaccordance with this invention while materials having pore volumes inexcess of 50 or 60% are also routinely attainable. It is preferred thatmaterials of the invention have pore volumes of at least about 75%. Morepreferred are materials having pore volumes in excess of about 85%, with90% being still more preferred. Pore volumes greater than about 92% arepossible as are volumes greater than about 94%. In some cases, materialswith pore volumes approaching 95% can be made in accordance with theinvention. In preferred cases, such high pore volumes are attained whilealso attaining the presence of macro- meso- and microporosity as well asphysical stability of the materials produced. It is believed to be agreat advantage to be able to prepare inorganic shaped bodies havingmacro-, meso- and microporosity simultaneously with high pore volumes asdescribed above.

[0098] It has now been found that such shaped bodies may be formed fromminerals in this way which have remarkable macro- and microstructures.In particular, a wide variety of different shapes can be formed andbodies can be prepared which are machinable, deformable, or otherwisemodifiable into still other, desired states. The shaped bodies havesufficient inherent physical strength allowing that such manipulationcan be employed. The shaped bodies can also be modified in a number ofways to increase or decrease their physical strength and otherproperties so as to lend those bodies to still further modes ofemployment. Overall, the present invention is extraordinarily broad inthat shaped mineral bodies may be formed easily, inexpensively, undercarefully controllable conditions, and with enormous flexibility.Moreover, the microstructure of the materials that can be formed fromthe present invention can be controlled as well, such that they may becaused to emulate natural bone, to adopt a uniform microstructure, to berelatively dense, relatively porous, or, in short, to adopt a widevariety of different forms. The ability to control in a predictable andreproducible fashion the macrostructure, microstructure, and mineralidentity of shaped bodies in accordance with the present invention underrelatively benign conditions using inexpensive starting materials lendsthe technologies of the present invention to great medical, chemical,industrial, laboratory, and other uses.

[0099] In accordance with certain preferred embodiments of the presentinvention, a reactive blend in accordance with the invention is causedto be imbibed into a material which is capable of absorbing it. It ispreferred that the material have significant porosity, be capable ofabsorbing significant amounts of the reactive blend via capillaryaction, and that the same be substantially inert to reaction with theblend prior to its autologous oxidation-reduction reaction. It has beenfound to be convenient to employ sponge materials, especially cellulosesponges of a kind commonly found in household use for this purpose.Other sponges, including those which are available in compressed formsuch as Normandy sponges, are also preferred in certain embodiments. Thesubstrate used to imbibe the reactive blend, however, are not limited toorganic materials and can include inorganic materials such asfiberglass.

[0100] The sponges are caused to imbibe the reactive blend in accordancewith the invention and are subsequently, preferably blotted to removeexcess liquid. The reactive blend-laden sponge is then heated towhatever degree may be necessary to initiate the oxidation-reductionreaction of the reactive blend. Provision is generally made for theremoval of by-product noxious gases, chiefly nitrogen oxide gases, fromthe site of the reaction. The reaction is exothermic, however the entirereacted body does not generally exceed a few hundred degrees centigrade.In any event, the reaction goes to completion, whereupon what is seen isan object in the shape of the original sponge which is now intimatelycomprised of the product of the oxidation reduction reaction. Thismaterial may either be the finished, desired mineral, or may be aprecursor from which the desired product may be obtained by subsequentPROCESSING.

[0101] Following the initial oxidation-reduction reaction, it isconvenient and, in many cases, preferred to heat treat the reactedproduct so as to eliminate the original sponge. In this way, thecellulosic component of the sponge is pyrolyzed in a fugitive fashion,leaving behind only the mineral and in some cases, a small amount ofash. The resulting shaped body is in the form of the original sponge andis self-supporting. As such, it may be used without furthertransformation or it may be treated in one or more ways to change itschemical and or physical properties. Thus, the shaped body following theoxidation-reduction reaction, can be heat treated at temperatures offrom about 250° C. to about 1400° C., preferably from 500° C. to about1000° C., and still more preferably from about 500° C. to about 800° C.Thus, a precursor mineral formed from the oxidation-reduction reactionmay be transformed into the final mineral desired for ultimate use. Anumber of such transformations are described in the examples to thepresent application and still others will readily occur to personsskilled in the art.

[0102] It will be appreciated that temperatures in excess of 250° C. maybe employed in initiating the oxidation-reduction reaction and, indeed,any convenient temperature may be so utilized. Moreover, methods ofinitiating the reaction where the effective temperature is difficult orimpossible to determine, such a microwave heating, may, also beemployed. The preferred procedures, however, are to employ reactionconditions to initiate, and propagate if necessary, the reaction arebelow the temperature wherein melting of the products occur. This is indistinction with conventional glass and ceramic processing methods.

[0103] The shaped bodies thus formed may be used in a number of waysdirectly or may be further modified. Thus, either the as-formed productof the oxidation-reduction reaction may be modified, or a resulting,transformed mineral structure may be modified, or both. Various naturaland synthetic polymers, pre-polymers, organic materials, metals andother adjuvants may be added to the inorganic structures thus formed.Thus, wax, glycerin, gelatin., pre-polymeric materials such asprecursors to various nylons, acrylics, epoxies, polyalkylenes, and thelike, may be caused to permeate all or part of the shaped bodies formedin accordance with the present invention. These may be used to modifythe physical and chemical nature of such bodies. In the case ofpolymers, strength modifications may easily be obtained. Additionally,such materials may also change the chemical nature of the minerals, suchas by improving their conductivity, resistance to degradation,electrolytic properties, electrochemical properties, catalyticproperties, or otherwise. All such modifications are contemplated by thepresent invention.

[0104] As will be appreciated, the shaped bodies prepared in accordancewith the present invention may be formed in a very large variety ofshapes and structures. It is very easy to form cellulose sponge materialinto differing shapes such as rings, rods, screw-like structures, andthe like. These shapes, when caused to imbibe a reactive blend, willgive rise to products which emulate the original shapes. It is alsoconvenient to prepare blocks, disks, cones, frustrums or other grossshapes in accordance with the present invention which shapes can bemachined, cut, or otherwise manipulated into a final desiredconfiguration. Once this has been done, the resulting products may beused as is or may be modified through the addition of gelatin, wax,polymers, and the like, and used in a host of applications.

[0105] When an inherently porous body such as a sponge is used as asubstrate for the imbibition of reactive blend and the subsequentelaboration of oxidation-reduction product, the resulting productreplicates the shape and morphology of the sponge. Modifications in theshape of the sponge, and in its microstructure can give rise tomodifications in at least the intermediate structure and grossstructures of the resulting products. It has been found, however, thatthe microstructure of shaped bodies prepared in accordance with thepresent invention frequently include complex and highly desirablefeatures. Thus, on a highly magnified scale, microstructure of materialsproduced in accordance with the present invention can show significantmicroporosity. In several embodiments of the present invention, themicrostructure can be custom-tailored based upon the absorbent materialselected as the fugitive support. One particular embodiment, which useda kitchen sponge as the absorbent material, exhibited a macro- andmicrostructure similar to the appearance of ovine trabecular bone. Thishighly surprising, yet highly desirable result gives rise to obviousbenefits in terms of the replication of bony structures and to the useof the present invention in conjunction with the restoration of bonytissues in animals and especially in humans.

[0106] Other macro- and microstructures may be attained through thepresent invention, however. Thus, through use of the embodiments of thepresent invention, great diversity may be attained in the preparation ofmineral structures not only on a macroscopic but also on a microscopiclevel. Accordingly, the present invention finds utility in a widevariety of applications. Thus, the shaped bodies may be used inmedicine, for example for the restoration of bony defects and the like.The materials may also be used for the delivery of medicaments internalto the body. In this way, the porosity of a material formed inaccordance with the invention may be all or partially filled withanother material which either comprises or carries a medicament such asa growth hormone, antibiotic, cell signaling material, or the like.Indeed, the larger porous spaces within some of the products of thepresent invention may be used for the culturing of cells within thehuman body. In this regard, the larger spaces are amenable to the growthof cells and can be permeated readily by bodily fluids such as certainblood components. In this way, growing cells may be implanted in ananimal through the aegis of implants in accordance with the presentinvention. These implants may give rise to important biochemical ortherapeutic or other uses.

[0107] The present invention can call for the use of therapeuticmaterials. Replicated bone marrow or other types of bioengineered bonemarrow material can be used in this invention. Therapeutic materials canalso be used for the delivery of healing materials, such as medicaments,internal to the body. Such medicaments can be growth hormones,antibiotics, or cell signals. Medicaments also may include steroids,analgesics, or fertility drugs. Exemplary therapeutic materials includesignaling molecules under the Transforming Growth Factor (TGF)Superfamily of proteins, specifically proteins under the TGF-beta(TGF-β), Osteogenic Protein (OP)/Bone Morphogenic Protein (BMP), VEGF(VEGF-1 and VEGF-2 proteins) and Inhibin/activtin (Inhibin-beta A,Inhibin-beta B, Inhibin-alpha, and MIS proteins) subfamilies. Mostpreferably, the exemplary therapeutic materials are proteins under theTGF-β and OP/BMP subfamilies. The TGF-β subfamily includes the proteinsBeta-2, Beta-3, Beta-4 (chicken), Beta-1, Beta-5 (xenopus) and HIF-1alpha. The OP/BMP subfamily includes the proteins BMP-2, BMP-4, DPP,BMP-5, Vgr-1, OP-1/BMP-7, Drosophila 60A, GDF-1, Xenopus Vg-1 and BMP-3.Representative proteins of these types include: OP-1/rhBMP-7, rhBMP-2,IGF-1 (Insulin-like Growth Factor-1), TGF beta, MP52. Other proteins,genes and cells outside the TGF Superfamily may also be included in theexemplary types of therapeutic materials to be used in conjunction withthe present invention. These other proteins, genes and cells includePepGen P-15, LMP-1 (LIM Mineralized Protein-I gene), Chrysalin TP 508Synthetic Peptide, GAM (parathyroid hormone), rhGDF-5, cell lines andFGF (Fibroblast Growth Factor) such as BFGF (Basic Fibroblast GrowthFactor), FGF-A (Fibroblast Growth Factor Acidic), FGFR (FibroblastGrowth Factor Receptor) and certain cell lines such as osteosarcoma celllines. The therapeutic materials to be used with the present inventionmaterial may also be combinations of those listed above. Such mixturesinclude products like Ne-Osteo GFm (growth factor mixture), or mixturesof growth factors/proteins/genes/cells produced by devices such as AGF(Autologous Growth Factor), Symphony Platelet Concentrate System, andthe like.

[0108] The invention finds great utility in chemistry as well. Shapedbodies formed from the present invention may be formed to resemblesaddles, rings, disks, honeycombs, spheres, tubes, matrixes, and, inshort, a huge array of shapes, which shapes may be used for engineeringpurposes. Thus, such shapes may be made from minerals which incorporatecatalytic components such as rare earths, precious and base metals,palladium, platinum, Raney nickel and the like for catalytic use. Theseshapes may also be used for column packing for distillation and otherpurposes. Indeed, the shapes may be capable of serving a plurality ofuses at once, such as being a substrate for refluxing while acting as acatalyst at the same time.

[0109] The bodies of the present invention will also be suitable forchromatography and other separation and purification techniques. Thus,they may serve as substrates for mobile phases in the same way that acapillary suspends a gelatinous material for capillary gelelectrophoresis.

[0110] The present invention also provides filtration media. As isapparent, the porous structures of the present invention may serve asfilters. Due to the ability to formulate these shaped bodies in a widevariety of carefully controlled ways, some unique structures may beattained. Thus, an anigotropic membrane, as known to persons of ordinaryskill in the art, and frequently referred to as a “Michaels” membranemay be used for the imbibation of reactive blend in accordance with theinvention. Following redox reaction and removal of the membranousmaterial as a fugitive phase, the resulting inorganic structure is alsoanisotropic. It is thus possible to utilize materials and shaped bodiesin accordance with the present invention as an anisotropic but inorganicfiltration media. Since it is also possible to include a number ofinorganic materials therein, such filters may be caused to be inherentlybacteriostatic and non-fouling. It has been shown, heretofore, thatanisotropic membranes such as polysulfone and other membranes arecapable of nurturing and growing cells for the purposes of deliveringcellular products into a reaction screen. It is now possible toaccomplish the same goals using wholly inorganic structures prepared inaccordance with this invention.

[0111] In addition to the foregoing, it is possible to prepare andmodify shaped bodies in accordance with the present invention in avariety of other ways. Thus, the shaped bodies may be coated, such aswith a polymer. Such polymers may be any of the film forming polymers orotherwise and may be used for purposes of activation, conductivity,passivation, protection, or other chemical and physical modification.The bodies may also be contacted with a “keying agent” such as a silane,or otherwise to enable the grafting of different materials onto thesurface of the polymer.

[0112] The shaped bodies of the invention may also be used for thegrowth of oligomers on their surfaces. This can be done in a manneranalogous to a Merrifield synthesis, an oligonucleotide synthesis orotherwise. Such shaped bodies may find use in conjunction with automatedsyntheses of such oligomers and may be used to deliver such oligomers tothe body of an animal, to an assay, to a synthetic reaction vessel, orotherwise. Since the mineral composition of the shaped bodies of thisinvention may be varied so widely, it is quite suitable to theelaboration of oligomers as suggested here and above. Grafting of otherinorganic materials, silanes, especially silicones and similarmaterials, is a particular feature of the present invention. Thegrafting reactions, keying reactions, oligomer extension reactions andthe like are all known to persons skilled in the art and will not berepeated here. Suffice it to say that all such reactions are includedwithin the scope of the present invention.

[0113] The shaped bodies of the invention may also be coated throughsurface layer deposition techniques such as plasma coating, electrolessplating, chemical vapor deposition (CVD), physical vapor deposition(PVD), or other methods. In such a way, the surface structure of theshaped bodies may be modified in carefully controlled ways forcatalytic, electronic, and other purposes. The chemistry and physics ofchemical vapor deposition and other coating techniques are known topersons of ordinary skill in the art whose knowledge is hereby assumed.

[0114] In accordance with other embodiments of the invention, the shapedbodies produced hereby may be comminuted to yield highly useful andunique powder materials finding wide utility. Thus, shaped bodies may becrushed, milled, etc. and preferably classified or measured, such aswith a light scattering instrument, to give rise to fine powders. Suchpowders are very small and highly uniform, both in size, shape andchemical composition. Particles may be prepared having particle sizenumber means less than about 0.1 μm or 100 nanometers. Smaller meansized may also be attained. Thus, this invention provides highly uniforminorganic materials in powder form having particle sizes, measured bylight scattering techniques such that the number mean size is betweenabout 0.1 and 5.0 μm. Particle sizes between about 0.5 and 2.0 μm mayalso be attained. It may, in some embodiments, be desired to classifythe powders in order to improve uniformity of size.

[0115] The morphology of the particles is highly uniform, deriving, itis thought, from the microporosity of the shaped bodies from which theyarise. The particles are also highly uniform chemically. Since theyarise from a chemical reaction from a fully homogenous solution, suchuniformity is much greater than is usually found in glass or ceramicmelts.

[0116] Particle size number means are easily determined with a HoribaLA-910 instrument. Number means refers to the average or mean number ofparticles having the size or size range in question.

[0117] Such powders are very useful, finding use in cosmetics,pharmaceuticals, excipients, additives, pigments, fluorescing agents,fillers, flow control agents, thixotropic agents, materials processing,radiolabels, and in may other fields of endeavor. For example, a moldedgolf ball may easily be made such as via the processes of Bartsch,including a calcium phosphate powder of this invention admixed with acrosslinked acrylic polymer system.

[0118] In conjunction with certain embodiments of the present invention,shaping techniques are employed on the formed, shaped bodies of thepresent invention. Thus, such bodies may be machined, pressed, stamped,drilled, lathed, or otherwise mechanically treated to adopt a particularshape both externally and internally. As will be appreciated, theinternal microstructure of the bodies of the present invention can bealtered thru the application of external force where such modificationsare desired. Thus, preforms may be formed in accordance with theinvention from which shapes may be cut or formed. For example, anorthopaedic sleeve for a bone screw may be machined from a block ofcalcium phosphate made hereby, and the same tapped for screw threads orthe like. Carefully controllable sculpting is also possible such thatprecisely-machined shapes may be made for bioimplantation and otheruses.

[0119] While many of the present embodiments rely upon the imbibation ofreactive blends by porous, organic media such as sponges and the like,it should be appreciated that many other ways of creating shaped bodiesin accordance with this invention also exist. In some of theseembodiments, addition of materials, either organic or inorganic, whichserve to modify the characteristic of the reactive blend may bebeneficial. As an example of this, flow control agents may be employed.Thus, it may be desirable to admix a reactive blend in accordance withthe invention together with a material such as a carboxymethyl or othercellulose or another binding agent to give rise to a paste or slurry.This paste or slurry may then be formed and the oxidation reductionreaction initiated to give rise to particular shapes. For example,shaped bodies may be formed through casting, extrusion, foaming, doctorblading, spin molding, spray forming, and a host of other techniques. Itis possible to extrude hollow shapes in the way that certain forms ofhollow pasta are extruded. Indeed, machinery useful for the preparationof certain food stuffs may also find beneficial use in conjunction withcertain embodiments of the present invention. To this end, foodextrusion materials such as that used for the extrusion of “cheesepuffs” or puffed cereals may be used. These combine controllabletemperature and pressure conditions with an extrusion apparatus. Throughcareful control of the physical conditions of the machinery, essentiallyfinished, oxidation-reduction product may be extruded and used as-is orin subsequently modified form.

[0120] In accordance with certain embodiments, a film of reactive blendmay be doctored onto a surface, such as stainless steel or glass, andthe film caused to undergo an oxidation-reduction reaction. Theresulting material can resemble a potato chip in overall structure withvariable porosity and other physical properties.

[0121] In addition to the use of sponge material, the present inventionis also amenable to the use of other organic material capable ofimbibing reactive blend. Thus, if a gauze material is used, theresulting oxidation reduction product assumes the form of the gauze. Aflannel material will give rise to a relatively thick pad of inorganicmaterial from which the organic residue may be removed through theapplication of heat. Cotton or wool may be employed as may be a host ofother organic materials.

[0122] It is also possible to employ inorganic materials and even metalsin accordance with the present invention. Thus, inclusion of conductivemesh, wires, or conductive polymers in materials which form thesubstrate for the oxidation reduction of the reactive blend can giverise to conductive, mineral-based products. Since the minerals may beformed or modified to include a wide variety of different elements, thesame may be caused to be catalytic. The combination of a porous,impermeable, catalytic material with conductivity makes the presentinvention highly amenable to use in fuel cells, catalytic converters,chemical reaction apparatus and the like.

[0123] In this regard, since the conductive and compositional characterof the shaped bodies of the present invention may be varied inaccordance with preselected considerations, such shapes may be used inelectronic and military applications. Thus, the ceramics of theinvention may be piezoelectric, may be transparent to microwaveradiation and, hence, useful in radomes and the like. They may be ionresponsive and, therefore, useful as electrochemical sensors, and inmany other ways. The materials of the invention may be formulated so asto act as pharmaceutical excipients, especially when comminuted, as gasscrubber media, for pharmaceutical drug delivery, in biotechnologicalfermentation apparatus, in laboratory apparatus, and in a host of otherapplications.

[0124] As will be apparent from a review of the chemistry portion of thepresent specification, a very large variety of mineral species may beformed. Each of these may be elaborated into shaped bodies as describedhere and above. For example, transition metal phosphates including thoseof scandium, titanium, chromium, manganese, iron, cobalt, nickel,copper, and zinc may be elaborated into pigments, phosphors, catalysts,electromagnetic couplers, microwave couplers, inductive elements,zeolites, glasses, and nuclear waste containment systems and coatings aswell as many others.

[0125] Rare earth phosphates can form intercalation complexes,catalysts, glasses, ceramics, radiopharmaceuticals, pigments andphosphors, medical imaging agents, nuclear waste solidification media,electro-optic components, electronic ceramics, surface modificationmaterials and many others. Aluminium and zirconium phosphates, forexample, can give rise to surface protection coatings, abrasivearticles, polishing agents, cements, filtration products and otherwise.

[0126] Alkali and alkaline earth metal phosphates are particularlyamenable to low temperature glasses, ceramics, biomaterials, cements,glass-metal sealing materials, glass-ceramic materials includingporcelains, dental glasses, electro-optical glasses, laser glasses,specific refractive index glasses, optical filters and the like.

[0127] In short, the combination of easy fabrication, great variabilityin attainable shapes, low temperature elaboration, wide chemicalcomposition latitude, and the other beneficial properties of the presentinvention lend it to a wide variety of applications. Indeed, otherapplications will become apparent as the full scope of the presentinvention unfolds over time.

[0128] In accordance with the present invention, the minerals formedhereby and the shaped bodies comprising them are useful in a widevariety of industrial, medical, and other fields. Thus, calciumphosphate minerals produced in accordance with preferred embodiments ofthe present invention may be used in dental and orthopaedic surgery forthe restoration of bone, tooth material and the like. The presentminerals may also be used as precursors in chemical and ceramicprocessing, and in a number of industrial methodologies, such as crystalgrowth, ceramic processing, glass making, catalysis, bioseparations,pharmaceutical excipients, gem synthesis, and a host of other uses.Uniform microstructures of unique compositions of minerals produced inaccordance with the present invention confer upon such minerals wideutility and great “value added.” Indeed, submicron microstructure can beemployed by products of the invention with the benefits which accompanysuch microstructures.

[0129] Improved precursors provided by this invention yield lowerformation temperatures, accelerated phase transition kinetics, greatercompositional control, homogeneity, and flexibility when used inchemical and ceramic processes. Additionally, these chemically-derived,ceramic precursors have fine crystal size and uniform morphology withsubsequent potential for very closely resembling or mimicking naturaltissue structures found in the body.

[0130] Controlled precipitation of specific phases from aqueoussolutions containing metal cations and phosphate anions represents adifficult technical challenge. For systems containing calcium andphosphate ions, the situation is further complicated by the multiplicityof phases that may be involved in the crystallization reactions as wellas by the facile phase transformations that may proceed duringmineralization. The solution chemistry in aqueous systems containingcalcium and phosphate species has been scrupulously investigated as afunction of pH, temperature, concentration, anion character,precipitation rate, digestion time, etc. (P. Koutsoukos, Z. Amjad, M. B.Tomson, and G. H. Nancollas, “Crystallization of calcium phosphates. Aconstant composition study,” J. Am. Chem. Soc. 102: 1553 (1980); A. T.C. Wong. and J. T. Czemuszka, “Prediction of precipitation andtransformation behavior of calcium phosphate in aqueous media,” inHydroxyapatite and Related Materials, pp 189-196 (1994), CRC Press,Inc.; G. H. Nancollas, “In vitro studies of calcium phosphatecrystallization,” in Biomineralization—Chemical and BiochemicalPerspectives, pp 157-187 (1989)).

[0131] Solubility product considerations impose severe limitations onthe solution chemistry. Furthermore, methods for generating specificcalcium phosphate phases have been described in many technical articlesand patents (R. Z. LeGeros, “Preparation of octacalcium phosphate (OCP):A direct fast method.” Calcif. Tiss Lnt. 37: 194 (1985)) As discussedabove, none of this aforementioned art employs the present invention.

[0132] Several sparingly soluble calcium phosphate crystalline phases,so called “basic” calcium phosphates, have been characterized, includingalpha- and beta-tricalcium phosphate (α-TCP, β-TCP, Ca₃(PO₄)₂),tetracalcium phosphate (TTCP, Ca₄(PO₄)₂O), octacalcium phosphate (OCP,Ca₄H(PO₄)₃.-nH₂O, where 2<n<3), and calcium hydroxyapatite (HAp,Ca₅(PO₄)₃(OH)). Soluble calcium phosphate phases, so called “acidic”calcium phosphate crystalline phases, include dicalcium phosphatedihydrate (brushite -DCPD, CaHPO₄.H₂O), dicalcium phosphate anhydrous(monetite-DCPA, CaHPO₄), monocalcium phosphate monohydrate (MCPM, Ca(H₂PO₄)₂—H₂O), and monocalcium phosphate anhydrous (MCPA, Ca(H₂ PO₄)₂ ).These calcium phosphate compounds are of critical importance in the areaof bone cements and bone grafting materials. The use of DCPD, DCPA,α-TCP, β-TCP, TTCP, OCP, and HAp, alone or in combination, has been welldocumented as biocompatible coatings, fillers, cements, and bone-formingsubstances (F. C. M. Driessens, M. G. Boltong, O. Bermudez, J. A.Planell, M. P. Ginebra, and E. Fernandez, “Effective formulations forthe preparation of calcium phosphate bone cements,” J. Mat. Sci.: Mat.Med. 5: 164 (1994); R. Z. LeGeros, “Biodegradation and bioresorption ofcalcium phosphate ceramics,” Clin. Mat. 14(1): 65 (1993); K. Ishikawa,S. Takagi, L. C. Chow, and Y. Ishikawa, “Properties and mechanisms offast-setting calcium phosphate cements,” J. Mat. Sci.: Mat. Med. 6: 528(1995); A. A. Mirtchi, J. Lemaitre, and E. Munting, “Calcium phosphatecements: Effect of fluorides on the setting and hardening ofbeta-tricalcium phosphate—dicalcium phosphate—calcite cements,” Biomat.12: 505 (1991); J. L. Lacout, “Calcium phosphate as bioceramics,” inBiomaterials—Hard Tissue Repair and Replacement, pp 81-95 (1992),Elsevier Science Publishers).

[0133] Generally, these phases are obtained via thermal or hydrothermalconversion of (a) solution-derived precursor calcium phosphatematerials, (b) physical blends of calcium salts, or (c) natural coral.Thermal transformation of synthetic calcium phosphate precursorcompounds to TCP or TTCP is achieved via traditional ceramic processingregimens at high temperature, greater than about 800° C. Thus, despitethe various synthetic pathways for producing calcium phosphateprecursors, the “basic” calcium phosphate materials used in the art(Ca/P≧1.5) have generally all been subjected to a high temperaturetreatment, often for extensive periods of time. For other preparationsof “basic” calcium phosphate materials, see also H. Monma, S. Ueno, andT. Kanazawa, “Properties of hydroxyapatite prepared by the hydrolysis oftricalcium phosphate,” J. Chem. Tech. Biotechnol. 31: 15 (1981); H.Chaair, J. C. Heughebaert, and M. Heughebaert, “Precipitation ofstoichiometric apatitic tricalcium phosphate prepared by a continuousprocess,” J. Mater. Chem. 5(6): 895 (1995); R. Famery, N. Richard, andP. Boch, “Preparation of alpha- and beta-tricalcium phosphate ceramics,with and without magnesium addition,” Ceram. Int. 20: 327 (1994); Y.Fukase, E. D. Eanes, S. Takagi, L. C. Chow, and W. E. Brown, “Settingreactions and compressive strengths of calcium phosphate cements,” J.Dent. Res. 69(12): 1852 (1990).

[0134] The present invention represents a significant departure fromprior methods for synthesizing metal phosphate minerals and porousshaped bodies of these materials, particularly calcium phosphate powdersand materials, in that the materials are formed from homogeneoussolution using a novel Redox Precipitation Reaction (RPR). They can besubsequently converted to TCP, HAp and/or combinations thereof at modesttemperatures and short firing schedules. Furthermore, precipitation fromhomogeneous solution (PFHS) in accordance with this invention, has beenfound to be a means of producing particulates of uniform size andcomposition in a form heretofore not observed in the prior art.

[0135] The use of hypophosphite [H₂PO₂ ⁻] anion as a precursor tophosphate ion generation has been found to be preferred since itcircumvents many of the solubility constraints imposed by conventionalcalcium phosphate precipitation chemistry and, furthermore, it allowsfor uniform precipitation at high solids levels. For example, reactionscan be performed in accordance with the invention giving rise to productslurries having in excess of 30% solids. Nitrate anion is the preferredoxidant, although other oxidizing agents are also useful.

[0136] The novel use of nitrate anion under strongly acidic conditionsas the oxidant for the hypophosphite to phosphate reaction is beneficialfrom several viewpoints. Nitrate is readily available and is aninexpensive oxidant. It passivates stainless steel (type 316 SS) and isnon-reactive to glass processing equipment. Its oxidation byproducts(NO_(x)) are manageable via well-known pollution control technologies,and any residual nitrate will be fugitive, as NO_(x) under the thermalconversion schedule to which the materials are usually subjected, thusleading to exceedingly pure final materials.

[0137] Use of reagent grade metal nitrate salts and hypophosphorousacid, as practiced in this invention, will lead to metal phosphatephases of great purity.

[0138] Methods for producing useful calcium phosphate-based materialsare achieved by reduction-oxidation precipitation reactions (RPR)generally conducted at ambient pressure and relatively low temperatures,usually below 250° C. and preferably below 200° C., most preferablybelow 150° C. The manner of initiating such reactions is determined bythe starting raw materials, their treatment, and the redoxelectrochemical interactions among them.

[0139] The driving force for the RPR is the concurrent reduction andoxidation of anionic species derived from solution precursors.Advantages of the starting solutions can be realized by the high initialconcentrations of ionic species, especially calcium and phosphorusspecies. It has been found that the use of reduced phosphorus compoundsleads to solution stability at ionic concentrations considerably greaterthan if fully oxidized [PO₄]⁻³ species were used. Conventionalprocessing art uses fully oxidized phosphorus oxoanion compounds and is,consequently, hindered by pH, solubility, and reaction temperatureconstraints imposed by the phosphate anion.

[0140] Typical reducible species are preferably nitric acid, nitratesalts (e.g. Ca(NO₃)₂4H₂O), or any other reducible nitrate compound,which is highly soluble in water. Other reducible species includenitrous acid (HNO₂) or nitrite (NO₂ ⁻) salts.

[0141] Among the oxidizable species which can be used arehypophosphorous acid or hypophosphite salts [e.g. Ca(H₂ PO₂)₂] which arehighly soluble in water. Other oxidizable species which find utilityinclude acids or salts of phosphites (HPO₃ ²⁻), pyrophosphites (H₂P₂O₅²⁻), thiosulfate (S₂O₃ ²⁻), tetrathionate (S₄O₆ ²⁻), dithionite (S₂O₄²⁻) trithionate (S_(3O) ₆ ²⁻), sulfite (SO₃ ²⁻), and dithionate (S₂O₆²⁻). In consideration of the complex inorganic chemistry of theoxoanions of Groups 5B, 6B, and 7B elements, it is anticipated thatother examples of oxidizable anions can be utilized in the spirit ofthis invention.

[0142] The cation introduced into the reaction mixture with either orboth of the oxidizing or reducing agents are preferably oxidativelystable (i.e. in their highest oxidation state). However, in certainpreparations, or to effect certain reactions, the cations may beintroduced in a partially reduced oxidation state. Under thesecircumstances, adjustment in the amount of the oxidant will be necessaryin order to compensate for the electrons liberated during the oxidationof the cations during RPR.

[0143] It is well known in the art that for solutions in equilibriumwith ionic precipitates, the solute concentrations of the reactant ionsare dictated by solubility product relationships and supersaturationlimitations. For the Ca²⁺—[PO₄]⁻³ system, these expressions areexceedingly complicated, due in large part to the numerous pathways(i.e., solid phases) for relieving the supersaturation conditions.Temperature, pH, ionic strength, ion pair formation, the presence ofextraneous cations and anions all can affect the various solute speciesequilibria and attainable or sustainable supersaturation levels (F.Abbona, M. Franchini-Angela, and R. Boistelle, “Crystallization ofcalcium and magnesium phosphates from solutions of medium and lowconcentrations,” Cryst. Res. Technol. 27: 41 (1992); G. H. Nancollas,“The involvement of calcium phosphates in biological mineralization anddemineralization processes,” Pure Appl. Chem. 64(11): 1673 (1992); G. H.Nancollas and J. Zhang, “Formation and dissolution mechanisms of calciumphosphates in aqueous systems,” in Hydroxyapatite and Related Materials,pp 73-81 (1994), CRC Press, Inc.; P. W. Brown, N. Hocker, and S. Hoyle,“Variations in solution chemistry during the low temperature formationof hydroxyapatite,” J. Am. Ceram. Soc. 74(8): 1848 (1991); G. Vereeckeand J. Lemaitre, “Calculation of the solubility diagrams in the systemCa(OH)₂—H₃PO₄—KOH—HNO₃—CO₂—H₂O, ” J. Cryst. Growth 104: 820 (1990); A.T. C. Wong and J. T. Czernuszka, “Prediction of precipitation andtransformation behavior of calcium phosphate in aqueous media,” inHydroxyapatite and Related Materials, pp 189-196 (1994), CRC Press,Inc.; G. H. Nancollas, “In vitro studies of calcium phosphatecrystallization,” in Biomineralization—Chemical and BiochemicalPerspectives, pp 157-187 (1989)).

[0144] Additionally, while thermodynamics will determine whether aparticular reaction is possible, kinetic effects may be very much moreimportant in explaining the absence or presence of particular calciumphosphate phases during precipitation reactions.

[0145] In the practice of certain preferred embodiments of thisinvention to give rise to calcium phosphates, soluble calcium ion ismaintained at concentrations of several molar in the presence of solublehypophosphite anion which is, itself, also at high molar concentrations.The solution is also at a very low pH due to the presence of nitric andhypophosphorous acids. Indeed, such solutions of calcium andhypophosphite ions can be stable indefinitely with respect toprecipitation, at room temperature or below. In contrast, it isimpossible (in the absence of ion complexation or chelating agents) tosimultaneously maintain calcium ions and phosphate anions at similarconcentrations as a solid phase would immediately precipitate to relievethe supersaturation. Upon oxidation of the hypophosphite ion tophosphite and, subsequently, to phosphate, calcium phosphate phases arerapidly precipitated from homogeneous solution under solution conditionsunique (concentration, pH, ionic strength) for the formation of suchmaterials. The combination of homogeneous generation of precipitatinganion, rapid precipitation kinetics, and unique thermodynamic regimeresults in the formation of calcium phosphate precursors having uniquesize and morphological characteristics, surface properties, andreactivities.

[0146] The foregoing consideration will also apply to minerals otherthan the calcium phosphates. Perforce, however, the phase diagrams,equilibrium conditions and constituent mineral phases will differ ineach family of minerals.

[0147] Uniformly sized and shaped particles of metal salts comprised ofone or more metal cations in combination with one or more oxoacid anionscan result from the present general method for the controlledprecipitation of said metal salts from aqueous solutions. These proceedvia the in situ homogeneous production of simple or complex oxoacidanions of one or more of the nonmetallic elements, Group 5B and 6B(chalcogenides), and 7B (halides). The first oxoacid anion undergoesoxidation (increase in chemical oxidation state) to generate theprecipitant anionic species along with concurrent reduction (decrease inchemical oxidation state) of the nonmetallic element of a second,dissimilar oxoacid anion, all oxoacid anions initially being present insolution with one or more metal cations known to form insoluble saltswith the precipitant anion. The metal cations are, preferably,oxidatively stable, but may undergo oxidation state changes themselvesunder certain conditions.

[0148] RPR is induced preferably by heating a homogeneous solution, soas to promote the onset and continuation of an exothermic redoxreaction. This exothermic reaction results in the generation of gases,usually various nitrogen oxide gases such as NO_(x), where 0.5<x<2, asthe soluble reduced phosphorus species are converted to precipitatinganions which then homogeneously precipitate the calcium ions from thereaction medium. At this stage, the reaction is substantially complete,resulting in an assemblage of ultrafine precipitated particles of thepredetermined calcium-phosphate stoichiometry. The reaction yield ishigh as is the purity of the reaction products.

[0149] The use of alternate heating methods to initiate and complete theRPR reaction may offer utility in the formation of scaffold structures.One such power source is microwave energy, as found in conventional600-1400W home microwave ovens. The benefit of the use of microwaves isthe uniformity of the heating throughout the entire reaction mass andvolume as opposed to the external-to-internal, thermal gradient createdfrom traditional conduction/convection/radiant heating means. The rapid,internal, uniform heating condition created by the use of microwaveenergy provides for rapid redox reaction initiation and drying. Theexcess RPR liquid is expelled to the outer surface of the cellulose bodyand flashes off to form an easily removed deposit on the surface. Therapid rate of heating and complete removal of the fugitive substructurealters the particulate structure resulting in greater integral strength.The speed of heating and initiation of the RPR reaction may alsominimize crystal grain growth. Intermediate precursor mineral powdersare homogeneously precipitated from solution. Moderate heat treatmentsat temperatures <500° C., can be used to further the transformation tovarious phosphate containing phases. Proper manipulations of chemistryand process conditions have led to mono- and multiphasic compounds withunique crystal morphologies, see, e.g. FIGS. 1 and 2.

[0150] The nitrate/hypophosphite redox system involves a hypophosphiteoxidation to phosphate (p⁺¹ to p⁺⁵, a 4e⁻ oxidation) as depicted in thefollowing equations (E₀/V from N. N. Greenwood and A. Earnshaw,“Oxoacids of phosphorus and their salts,” in Chemistry of the Elements,pp 586-595 (1984), Pergamon Press): Reduction potential at pH 0, 25° C.Reaction E_(O)/V H₃PO₃ + 2H⁺ + 2e⁻ = H₃PO₂ + H₂O −0.499 (1) H₃PO₄ =2H⁺ + 2e⁻ = H₃PO₃ + H₂O −0.276 (2) H₃PO₄ + 4H⁺ + 4e⁻ = H₃PO₂ + H₂O−0.775 Overall (3)

[0151] and a nitrate reduction to NO_(x) (N⁺⁵ to N⁺³ or N⁺², either a2e⁻ or a 3e⁻ reduction) as depicted in the following equations:Reduction potential at pH 0, 25° C. Reaction E_(O)/V 2NO₃ ⁻ + 4H⁺ + 2e⁻= N₂O₄ + 2H₂O 0.803 (4) NO₃ ⁻ + 3H⁺ + 2e⁻ = HNO₂ + H₂O 0.94  (5) NO₃ +4H⁺ + 3e⁻ = NO + 2H₂O 0.957 (6)

[0152] Chemical reactions are conveniently expressed as the sum of two(or more) electrochemical half-reactions in which electrons aretransferred from one chemical species to another. According toelectrochemical convention, the overall reaction is represented as anequilibrium in which the forward reaction is stated as a reduction(addition of electrons), i.e.:

Oxidized species+ne⁻=Reduced species

[0153] For the indicated equations at pH=0 and 25° C., the reaction isspontaneous from left to right if E₀ (the reduction potential) isgreater than 0, and spontaneous in the reverse direction if E_(o) isless than 0.

[0154] From the above reactions and associated electrochemicalpotentials, it is apparent that nitrate is a strong oxidant capable ofoxidizing hypophosphite (P⁺¹) to phosphite (p⁺³) or to phosphate (P⁺⁵)regardless of the reduction reaction pathway, i.e., whether thereduction process occurs according to Equation 4, 5, or 6. If an overallreaction pathway is assumed to involve a combination of oxidationreaction (Eq.3) (4e⁻ exchange) and reduction reaction (Eq.6) (3e⁻exchange), one can calculate that in order for the redox reaction toproceed to completion, 4/3 mole of NO₃ ⁻ must be reduced to NO per moleof hypophosphite ion to provide sufficient electrons. It is obvious toone skilled in the art that other redox processes can occur involvingcombinations of the stated oxidation and reduction reactions.

[0155] Different pairings of oxidation and reduction reactions can beused to generate products according to the spirit of this invention.Indeed, the invention generally allows for the in situ homogeneousproduction of simple or complex oxoacid anions in aqueous solution inwhich one or more nonmetallic elements such as Group 5B and 6B(chalcogenuides), and 7B (halides) comprising the first oxoacid anionundergoes oxidation to generate the precipitant anionic species alongwith concurrent reduction of the nonmetallic element of a second,dissimilar oxoacid anion.

[0156] In each of the above scenarios, the key is thereduction-oxidation reaction at high ionic concentrations leading to thehomogenous precipitation from solution of novel calcium phosphatepowders. Never before in the literature has the ability to form suchphases, especially calcium-phosphate phases, been reported under theconditions described in this invention.

[0157] Specific embodiments of the invention utilize the aforementionedprocesses to yield unique calcium phosphate precursor minerals that canbe used to form a self-setting cement or paste. Once placed in the body,these calcium phosphate cements (CPC) will be resorbed and remodeled(converted) to bone. A single powder consisting of biphasic minerals ofvarying Ca/P ratio can be mixed to yield self-setting pastes thatconvert to type-B carbonated apatite (bone mineral precursor) in vivo.

[0158] The remodeling behavior of a calcium phosphate bioceramic to boneis dictated by the energetics of the surface of the ceramic and theresultant interactions with osteoclastic cells on approach to theinterface. Unique microstructures can yield accelerated reactivity and,ultimately, faster remodeling in vivo. The compositional flexibility inthe fine particles of this invention offers adjustable reactivity invivo. The crystallite size and surface properties of the resultantembodiments of this invention are more similar to the scale expected andfamiliar to the cells found in the body. Mixtures of powders derivedfrom the processes of this invention have tremendous utility as calciumphosphate cements (CPCs).

[0159] An aqueous solution can be prepared in accordance with thepresent invention and can be imbibed into a sacrificial organicsubstrate of desired shape and porosity, such as a cellulose sponge. Thesolution-soaked substrate is subjected to controlled temperatureconditions to initiate the redox precipitation reaction. After the redoxprecipitation reaction is complete, a subsequent heating step isemployed to combust any remaining organic material and/or promote phasechanges. The resultant product is a porous, inorganic material whichmimics the shape, porosity and other aspects of the morphology of theorganic substrate.

[0160] It is anticipated that the porous inorganic materials of thepresent invention would be suitable for a variety of applications. FIG.3 depicts a discoidal filter scaffold 16, which is prepared inaccordance with the present invention, and enclosed within an exteriorfilter housing 18 for filtration or bioseparation applications.Depending upon its end use, discoidal filter scaffold 16 can be abiologically active, impregnated porous scaffold. Arrow 20 representsthe inlet flow stream. Arrow 22 represents the process outlet streamafter passing through discoidal filter scaffold 16.

[0161]FIG. 4 illustrates a block of the porous inorganic material thatis used as a catalyst support within a two stage, three way hot gasreactor or diffusor. Items 30 and 32 illustrate blocks of the porousmaterial used as catalytically impregnated scaffolds. Items 30 and 32may be composed of the same or different material. Both 30 and 32,however, are prepared in accordance with an embodiment of the presentinvention. Item 34 depicts the first stage catalyst housing, which maybe comprised of a ferrous-containing material, and encloses item 30.Item 36 depicts the second stage catalyst housing, which may becomprised of a ferrous-containing material, and encloses item 32. Item38 represents the connector pipe, which is comprised of the samematerial as the housings 34 and 36, and connects both 34 and 36. Arrow40 represents the raw gas inlet stream prior to passing through bothblocks of catalytically impregnated scaffold (items 30 and 32). Arrow42, lastly, represents the processed exhaust gas stream.

[0162] In other embodiments of the present invention, the inorganicporous material is a calcium phosphate scaffolding material that may beemployed for a variety of uses. FIG. 5 illustrates a block of thecalcium phosphate scaffolding material 55 that may be inserted into ahuman femur and used for cell seeding, drug delivery, proteinadsorption, growth factor introduction or other biomedical applications.Femoral bone 51 is comprised of metaphysis 52, Haversian canal 53,diaphysis 54 and cortical bone 56. The calcium phosphate scaffoldingmaterial 55 is inserted into an excavation of the femoral bone as shownand ties into the Haversian canal allowing cell seeding, drug delivery,or other applications. Scaffolding material 55 can be used in the samemanner in a variety of human or mammalian bones.

[0163]FIG. 6A shows the calcium phosphate material of the presentinvention formed into the shape of a calcium phosphate sleeve 60. Item62 depicts the excavated cavity which can be formed via machining orother means. Item 64 presents a plurality of threads which can be coatedwith bioactive bone cement. FIG. 6B shows the calcium phosphate sleeve60 inserted into the jaw bone 66 and gum 67. The calcium phosphatesleeve 60 may be fixed in place via pins, bone cement, or othermechanical means of adhesion. An artificial tooth or dental implant 68can then be screwed into sleeve 60 by engaging threads 64.

[0164]FIG. 7A shows the porous, calcium phosphate scaffolding material70, prepared in accordance with an embodiment of the present invention,which is machined or molded to patient specific dimensions. FIG. 7Bdepicts the use of the material 70 that is formed into the shape ofcraniomaxillofacial implant 76, a zygomatic reconstruction 72, or amandibular implant 74.

[0165]FIG. 8A depicts a plug of the porous, calcium phosphatescaffolding material 80. FIG. 8B illustrates plug 80 which is insertedinto an excavation site 83 within a human knee, below the femur 81 andabove the tibia 82, for use in a tibial plateau reconstruction. Plug 80is held in place or stabilized via a bone cement layer 84.

[0166]FIG. 9 shows the calcium phosphate scaffolding material within ahuman femur that is used as a block 92 for bulk restoration or repair ofbulk defects in metaphyseal bone or oncology defects, or as a sleeve 94for an orthopaedic screw, rod or pin 98 augmentation. Item 99 depicts anorthopaedic plate anchored by the orthopaedic device item 98. Bonecement layer 96 surrounds and supports sleeve 94 in place.

[0167] Lastly, FIGS. 10A and 10B depict the use of the calcium phosphatescaffolding material as a receptacle sleeve 100 that is inserted intothe body to facilitate a bipolar hip replacement. Alternatively, thereceptacle sleeve may be comprised of other materials known in the art.Cavity 102 is machined to accommodate the insertion of a metallic balljoint implant or prosthesis 103. An orthopaedic surgeon drills a cavityor furrow into the bone 101 to receive sleeve 100. Sleeve 100 is thenaffixed to the surrounding bone via a bioactive or biocompatible bonecement layer 104 or other means. On the acetabular side, a femoral headarticulation surface 106 is cemented to a bone cement layer 104 thatresides within a prepared cavity with material of the present invention,100. A high molecular weight polyethylene cup, 105 is used to facilitatearticulation with the head of the prosthesis 103. The metallic balljoint implant or prosthesis 103 is thus inserted into a high molecularweight polyethylene cup 105 to facilitate joint an movement.

[0168] Orthopaedic appliances such as joints, rods, pins, sleeves orscrews for orthopaedic surgery, plates, sheets, and a number of othershapes may be formed from the calcium phosphate scaffolding material inand of itself or used in conjunction with conventional appliances thatare known in the art. Such porous inorganic bodies can be bioactive andcan be used, preferably, in conjunction with biocompatible gels, pastes,cements or fluids and surgical techniques that are known in the art.Thus, a screw or pin can be inserted into a broken bone in the same waythat metal screws and pins are currently inserted, using conventionalbone cements or restoratives in accordance with the present invention orotherwise. The bioactivity of the calcium phosphate scaffolding materialwill give rise to osteogenesis with beneficial medical or surgicalresults. For example, calcium phosphate particles and/or shaped bodiesprepared in accordance with this invention can be used in any of theorthopaedic or dental procedures known for the use of calcium phosphate;the procedures of bone filling defect repair, oncological defectfilling, craniomaxillofacial void filling and reconstruction, dentalextraction site filling, and potential drug delivery applications.

[0169] The scaffold structures of this invention, calcium phosphate inparticular, can be imbibed with blood, cells (e.g. fibroblasts,mesenchymal, stromal, marrow and stem cells), protein rich plasma otherbiological fluids and any combination of the above. Experiments havebeen conducted with ovine and canine blood (37° C.) showing the abilityof the scaffold to maintain its integrity while absorbing the blood intoits pores. This capability has utility in cell-seeding, drug delivery,and delivery of biologic molecules as well as in the application of bonetissue engineering, orthopaedics, and carriers of pharmaceuticals. Thismakes the Ca-P scaffold ideal for the use as an autograft extender orreplacement graft material.

[0170] The scaffold structures, especially calcium phosphate, can beimbibed with any bioabsorbable polymer or film-forming agent such aspolycaprolactones (PCL), polyglycolic acid (PGA), poly-L-Lactic acid(PL-LA), polysulfones, polyolefins, polyvinyl alcohol (PVA),polyalkenoics, polyacrylic acids (PAA), polyesters and the like.Experiments have been conducted with PCL, by solubilizing the PCL in anevaporative solvent and saturating a plug of calcium phosphate scaffoldstructure, allowing the structure to dry, and thus fixing the PCL ontothe surface and throughout the body of the scaffold. The resultant massis strong, carveable, and somewhat compressible. Experiments showed thatthe PCL coated material still absorbs blood. Numerous other uses forthese minerals and shaped bodies comprised thereof are anticipated. Theoxidizing agents, reducing agents, ratios, co-reactants and otheradducts, products and exemplary uses will be understood by inorganicchemists from a review of the aforementioned chemical reactions. Calciumphosphates are indicated for biological restorations, dentalrestorations, bioseparations media, and ion or protein chromatography.Transition metal phosphates (Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn)and shaped, porous articles thereof have numerous potential uses aspigments, phosphors, catalysts, electromagnetic couplers, microwavecouplers, inductive elements, zeolites, glasses, nuclear wastecontainment systems, radomes and coatings. Addition of rare-earthsphosphates can lead to uses as intercalation compounds, catalysts,catalyst support material, glasses and ceramics, radiopharmaceuticals,pigments and phosphors, medical imaging agents, nuclear wastesolidification, electro-optics, electronic ceramics, and surfacemodifications.

[0171] Aluminum and zirconium phosphates and shaped, porous articlesthereof are ideal candidates for surface protective coatings, abrasiveparticles, polishing agents, cements, and filtration products in eithergranular form or as coatings. The alkali (Na, K, Rb, Cs) andalkaline-earth (Be, Mg, Ca, Sr, Ba) phosphates and shaped, porousarticles thereof would generate ideal low temperature glasses, ceramics,biomaterials, cements, glass to metal seals, and other numerousglass-ceramic materials, such as porcelains, dental glasses,electro-optic glasses, laser glasses, specific refractive index glassesand optical filters. It is to be understood that the diverse chemistriesset forth herein may be applied to the creation of shaped bodies of theinvention.

[0172] It will be appreciated that, in accordance with certainembodiments of this invention, RPR-derived materials will be caused toexist on or in a first solid portion of material. The resultingcomposite structures offer highly desirable properties and are usefulfor a very wide range of applications. The RPR-derived portions of thecomposite shaped bodies of the invention form one portion of thosebodies. The other portion of the shaped bodies is comprised of another,solid material. The materials which can make up the non-RPR-derivedportion or portions of the shaped bodies can be any of a wide variety ofcompositions which are consistent with the overall objects of thisinvention. Thus, such materials may be metal, such as stainless steel,titanium, amalgam, silver, gold and the like. Metals stable to the humanbody are preferred although for non-surgical uses others can be employedas well. These materials may be ceramic or glass. In this context,bioactive glasses and ceramics are preferred. 45S5 glass materials areosteostimulatory and osteogenetic and can be used profitably in certainrestorations. Many ceramics are biostable, strong and well suited to usein this invention. Plastic materials may be the most flexible, howeverand will be preferred in many applications. In any event, any solidmaterial can form the non-RPR-derived portion or portions of the shapedbodies of the invention so long as they are stable to the intended useand to the RPR-derived material and can be formed or adhered therewith.

[0173] Of the polymers, the acrylics are preferred. Chief among thisclass for use with the present invention are acrylic polymers includinginorganic fillers. Any of this class, which is known per se, may beused. The preferred material is known as Orthocomp™ sold by OrthovitaCorporation of Malvern, Pa. Orthocomp™ is an acrylic having inorganicfiller. As part of the inorganic filler, the mineral Combeite isincluded. This filler system has been found to be biostable andbioactive. U.S. Pat. Nos. 5,681,872 and 5,914,356, assigned to theassignee of this invention, are directed to materials of this class andare incorporated herein by reference as if set forth in full. Thesepolymers are easily worked with, are hard, strong and bioactive.

[0174] It will be appreciated that during formation, RPR-derivedmaterials may, indeed, be formed in conjunction with another solidmaterial, e.g. sponge, glass or metal surfaces and the like. In general,the RPR material is removed from such solid material prior to furtheremployment. Thus, the sponge can be pyrolyzed, the RPR material removedfrom metal or glass plates after formation and the like. The solidmaterials used in this fashion are used to facilitate formation of theRPR material. While, in some cases, direct formation of RPR material incontact with a solid portion of dissimilar material may be performed inconnection with this invention, solid materials, such as spongiformmaterials, used solely for formation of RPR, which materials are removedprior to final fabrication or use, are not the kind of solid materialscontemplated hereby. Thus, the solid materials upon which theRPR-derived materials are to be found exclude solid materials which aremerely transitory.

[0175] The composite shaped bodies of the invention may be prepared inany convenient way. Thus a shape of RPR-derived material may be sprayed,dipped, brushed or otherwise coated with a polymerizable material,especially the Orthocomp™ material, and the same caused to polymerize.Alternatively, the RPR material may be formed around a core or layer ofother material such a polymer, metal, etc. A further option is for apolymeric, metallic ceramic or other shape to be prepared and filledwith RPR-derived material. Since the RPR-derived material does notrequire the application of high temperatures, this procedure is easilyapplicable to a host of embodiments.

[0176] Complex structures can be made. Thus, shaped bodies having three,four and more portions are useful for some embodiments of the invention.For example, a metal strut may be surrounded by RPR-derived calciumphosphate and the whole coated with Orthocomp™ or other polymer. Theresulting shaped body may be used in orthopaedic and other applications.Sandwich constructs like the “crouton” showed in FIG. 45 are also easilyprepared. Persons of skill in the art will have no difficulty inpreparing shaped bodies with the composite nature of the presentinvention.

[0177] Exemplary composite shaped bodies are shown in the drawings. FIG.29 depicts a pair of vertebrae 200 in a spine having a syntheticcortical ring 202 inserted therebetween. The vertebral ring has one ormore access ports 204 present an in communication with the interior ofthe ring. Injection of hardenable material via a syringe device 206 canbe accomplished via the port or ports. The hardenable material may beorganic, inorganic or mixed and is generally a bone cement or polymericbonding material.

[0178]FIG. 30 is a lateral view of a synthetic cortico-cancellousvertebral ring or interbody fusion device 202. In this embodiment, thering is composite, having a first portion 210 comprised of a firstmaterial and a second portion 212 comprised of a second material. Thematerial of the internal portion 212 is preferably RPR derived porous,inorganic calcium phosphate. FIG. 31 shows one embodiment of a syntheticcortical bone dowel in place. The dowel has a plurality of ports, someof which are shown 224. Hardenable material such as bone cement isinjected into the dowel, emerging from the ports to form a partialsurround of the dowel 228. FIG. 32 depicts another bone dowel for spinalfusion, The end of an injection device or syringe 226 is shown. Bonecement 224 is shown as well emerging from access ports 228 in the dowel.

[0179]FIG. 33 shows a synthetic cortical interbody vertebral defectfilling form. It, too may be employed with bone cement or otherwise.FIG. 34 is a cross sectional view of a bone dowel in place to accomplishspinal fusion. The dowel itself, 222, is shown potted within hardenablematerial 228 injected around and/or through the dowels.

[0180]FIGS. 35a through c depict synthetic cortical vertebral spacers orinterbody devices. Hard material, 240 preferably composite material inaccordance with the invention, forms the spacers and rings. In preferredembodiments a plurality of regions form a composite shaped body asillustrated in FIG. 35c. Hard material such as filled acrylic polymer240 forms an outer portion of the ring, while porous RPR-derivedmaterial, especially a calcium phosphate 242 forms an inner portion ofthe body.

[0181]FIGS. 36a through c depict synthetic cortical bone dowels orinterbody devices 250. The dowels may have access ports 252 foremergence of hardenable material when such material is injected intoorifice 254 with a syringe device. The dowels and devices may becomposite as set forth herein. FIG. 37 is another form of corticalspacer. The spacer has a relatively hard outer portion 260 and RPRderived inner portion 262. FIG. 38 is of a synthetic cancellous bonedowel. The dowel as depicted preferably has a heterogenous core materialsuch as a hard plastic, ceramic or metal.

[0182] The intervertebral body implants of FIGS. 30-34 and 35 a-36 c maybe used in conjunction with a sleeve. The sleeve may surround theconstruct to prevent leakage of the bone cement or calcium phosphatematerial placed within the construct.

[0183] The sleeve may be used alone or in conjunction with an outerdowel or ring to contain the material. If used alone, the sleeve formsthe outer portion of the construct and the bone cement or calciumphosphate forms the inner portion of the construct. The sleeve may becomprised of a variety of materials known in the art including metals,polymers or ceramics, and may be resorbable or non-resorbable.

[0184]FIG. 39 is a synthetic cortical vertebral interbody device ofanother form. An inner portion is formed of RPR derived calciumphosphate. FIGS. 40a and c are of synthetic cortico-cancellous defectfilling forms for bone restoration. Hard portion 270 is combined with anRPR-derived calcium phosphate portion 272 to give rise to thesecomposite shaped bodies. FIG. 40b is a cancellous defect filling formfor restoration. It is preferably formed from RPR-derived calciumphosphate 272 and preferably has a metallic, polymeric or ceramicunderlayment of support, not shown. FIG. 41a is drawn to acortico-cancellous bone dowel 280. Roughened area 282 is preferablyderived from RPR material. A port for access to the interior of thedowel 286 is provided. The Dowel preferably has heterogeneous supportportions in the interior.

[0185]FIG. 41b is another bone dowel 280 in different conformation.Injection port 286 communicate with the interior. Orifice 284 and otherstructure facilitates spread of bone cement.

[0186]FIG. 42 is a synthetic cortical ring. Hard outer ring structuremay either surround a void 292 or the void may be filled, e.g. withRPR-derived calcium phosphate material. The ring may also have innerportion formed from a heterogeneous material.

[0187]FIG. 43 is a cortical rod for orthopaedic restoration. FIG. 44 isa synthetic cortico-cancellous “tri-cortical” device for orthopaedicreconstructive surgery. Hard, preferably polymeric outer portionsubstantially 300 surrounds a porous inner structure 302, preferablyderived from RPR calcium phosphate. FIG. 45 depicts a cortico-cancellous“crouton” for orthopaedic surgery. Polymeric shell, preferably oneformed from bioactive polymer, 300, overlays a layer of RPR-derivedcalcium phosphate to form this composite shaped body. FIG. 46 is a“match stick” orthopaedic surgical splint. FIG. 47a and 47 b arecortical struts. They are preferably comprised of a plurality ofportions, one of which is an RPR-derived calcium phosphate.

[0188]FIGS. 48 and 49 show cortical rings having bioactive polymericouter portion 310 and RPR-derived calcium phosphate inner portion 312.FIGS. 50a and 50 b are cortical rings. These preferably haveheterogenous inner support or reinforcement portions. FIG. 51 depicts anartificial femur head for reconstructive surgery. Outer portion 320 ispreferably formed from hardened polymer while an inner portion 322 isRPR-derived calcium phosphate. This structure mimics natural bone

[0189]FIG. 52 is an artificial bone portion having hard outer portionand RPR-derived calcium phosphate inner portion. FIG. 53 is a strut ortube showing RPR-derived inner portion 322 surrounded by hardenedpolymer 320. FIG. 54 is a acetabular/pelvic form for orthopaedicreconstruction. The inner RPR structure 322 and outer polymeric portions320 are shown.

[0190]FIG. 55a and b depict insertion of a femoral hip dowel 330 into afemur, shown in phantom, requiring restoration. Access ports 332 permitthe injection of hardenable material, such as bone cement, into thedowel and, via the ports, around the dowel to effect fixation in thefemur head. FIGS. 56a through d are different forms of dowels 330 of thetype useful for hip or other reconstruction. Optional access ports 332are present in FIGS. 56b and 56 d.

EXAMPLES Example 1 Low Temperature Calcium Phosphate Powders

[0191] An aqueous solution of 8.51 g 50 wt % hypophosphorous acid, H₃PO₂(Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt %[PO₄]⁻³ was combined with 8.00 g distilled water to form a clear,colorless solution contained in a 250 ml Pyrex beaker. To this solutionwas added 22.85 g calcium nitrate tetrahydrate salt, Ca(NO₃)₂.4H₂O (ACSreagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4),equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 25.4wt %. Endothermic dissolution of the calcium nitrate tetrahydrateproceeded under ambient temperature conditions, eventually forming ahomogeneous solution. Warming of this solution above 25° C. initiated areaction in which the solution vigorously bubbled while evolvingred-brown acrid fumes characteristic of NO_(x(g)). The sample turnedinto a white, pasty mass which foamed and pulsed with periodic expulsionof NO_(x(g)). After approximately two minutes, the reaction wasessentially complete, leaving a white, pasty mass which was warm to thetouch. After cooling to room temperature, the solid (A) was stored in apolyethylene vial.

[0192] Three days after its preparation, a few grams of the damp, pastysolid were immersed in 30 ml distilled water in order to “wash out” anyunreacted, water soluble components. The solid was masticated with aspatula in order to maximize solid exposure to the water. Afterapproximately 15 minutes, the solid was recovered on filter paper andthe damp solid (B) stored in a polyethylene vial.

[0193] X-ray diffraction (XRD) patterns were obtained Tom packed powdersamples using the Cu-Kα line (λ=1.7889 Angstrom) from a RigakuGeigerflex instrument (Rigaku/USA, Inc., Danvers, Mass. 01923) run at 45kV/30 mA using a 2 degree/minute scan rate over the 20 angular rangefrom 15-50° or broader. Samples were run either as prepared or followingheat treatment in air in either a Thermolyne type 47900 or a Ney model3-550 laboratory furnace. XRD analysis of the samples yielded thefollowing results: Heat Major Minor Sample treatment phase phaseUnwashed (A) As prepared Undetermined — Unwashed (A) 300° C., 1 hourMonetite [CaHPO₄] — Unwashed (A) 500° C., 1 hour Whitlockite[β-Ca₃(PO₄)₂] CaH₂P₂O₇ Unwashed (A) 700° C., 1 hour Whitlockite[β-Ca₃(PO₄)₂] + HAp[Ca₅(PO₄)₃(OH)] Washed (B) As prepared Monetite[CaHPO₄] Washed (B) 100° C., 1 hour Monetite [CaHPO₄]

[0194] Additional amounts of NO_(x(g)) were evolved during firing of thesamples at or above 300° C.

[0195] A sample of the powder produced according to this Example wassubmitted to an outside laboratory for analysis (Coming, Inc.,CELS-Laboratory Services, Corning, N.Y. 14831). The results of thisoutside lab analysis confirmed that the powder fired at 700° C. wascomprised of whitlockite and hydroxyapatite.

Example 2 Low Temperature Calcium Phosphate Powder

[0196] Example 1 was repeated using five times the indicated weights ofreagents. The reactants were contained in a 5½″ diameter Pyrexcrystallizing dish on a hotplate with no agitation. Warming of thehomogeneous reactant solution above 25° C. initiated an exothermicreaction which evolved red-brown acrid fumes characteristic ofNO_(x(g)). Within a few seconds following onset of the reaction, thesample turned into a white, pasty mass which continued to expelNO_(x(g)) for several minutes. After approximately five minutes, thereaction was essentially complete leaving a damp solid mass which washot to the touch. This solid was cooled to room temperature underambient conditions for approximately 20 minutes and divided into twoportions prior to heat treatment.

[0197] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air, XRDindicated the fired solids to be composed of: Heat Major Minor Sampletreatment phase phase A 500° C., 1 hour Whitlockite HAp [Ca₅(PO₄)₃(OH)][β-Ca₃(PO₄)₂] B 700° C., 1 hour HAp [Ca₅(PO₄)₃(OH)] Whitlockite [β-Ca₃(PO₄)₂]

Example 3 Low Temperature Calcium Phosphate Powders

[0198] An aqueous solution of 8.51 g 50 wt % H₃PO₂ was combined with8.00 g of 25.0 wt % aqueous solution of calcium acetate monohydrate,Ca(O₂CCH₃)₂.H₂O (ACS reagent, Aldrich Chemical Co., Inc. #40,285-0, CAS5743-26-0), equivalent to 5.69 wt % Ca, to give a clear, colorlesssolution contained in a 250 ml Pyrex beaker. To this solution was added20.17 g Ca(NO₃)₂.4H₂O salt. The molar ratio of Ca/phosphate in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 27.3wt %. Endothermic dissolution of the calcium nitrate tetrahydrate saltproceeded giving a homogeneous solution once the sample warmed to roomtemperature. Further warming of this solution to >25° C. on a hotplateinitiated a reaction which proceeded as described in Example 1. Afterapproximately three minutes, the reaction was essentially completeleaving a moist, white, crumbly solid which was hot to the touch andwhich smelled of acetic acid. After cooling to room temperature, thesolid was stored in a polyethylene vial.

[0199] Heat treatment and X-ray diffraction analysis of this solid wereconducted as described in Example 1. Following heat treatment in air at500° C. for either 0.5 or 1 hour, XRD indicated the solid to be composedof whitlockite as the primary phase along with hydroxyapatite as thesecondary phase. XRD results indicate that the relative ratio of the twocalcium phosphate phases was dependent on the duration of the heattreatment and the presence of the acetate anion, but no attempts weremade to quantify the dependence. Heated to 500° C., 1 hour (Major)Whitlockite [β-Ca₃(PO₄)₂] (minor) Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH)

[0200] Comparing the XRD spectra from these results in Example 3 withXRD spectra from Example 1 shows the difference in the amount ofHAp-Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH) phase present for each minor phase. Thesamples in Example 1 exhibited no acetate whereas the samples in Example3 showed acetate present. This is indicative of the counteranion effecton crystal formation.

[0201] Fourier Transform Infrared (FTIR) spectra were obtained using aNicolet model 5DXC instrument (Nicolet Instrument Co., 5225 Verona Rd.Madison, Wis. 53744) run in the diffuse reflectance mode over the rangeof 400 to 4000 cm⁻¹. The presence of the carbonated form of HAp isconfirmed by the FTIR spectra, which indicated the presence of peakscharacteristic of [PO₄]⁻³ (580-600, 950-1250 cm⁻) and of [CO₃]⁻² (880,1400, & 1450 cm⁻¹). The P=O stretch, indicated by the strong peak at1150-1250 cm⁻¹, suggests a structural perturbation of hydroxyapatite bythe carbonate ion.

Example 4 Colloidal SiO₂ added to calcium phosphate mixtures via RPR

[0202] An aliquot of 8.00 g 34.0 wt % SiO₂ hydrosol (Nalco Chemical Co.,Inc. #1034A, batch #B5G453C) was slowly added to 8.51 g 50 wt % aqueoussolution of H₃PO₂ with rapid stirring to give a homogeneous, weaklyturbid colloidal dispersion. To this dispersion was added 22.85 gCa(NO₃)₂.4H₂O salt such that the molar ratio of calcium/phosphate in themixture was 3/2. Endothermic dissolution of the calcium nitratetetrahydrate proceeded giving a homogeneous colloidal dispersion oncethe sample warmed to room temperature. The colloidal SiO₂ was notflocculated despite the high acidity and ionic strength in the sample.Warming of the sample on a hotplate to >25° C. initiated a reaction asdescribed in Example 1. The resultant white, pasty solid was stored in apolyethylene vial.

[0203] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 1.0 hour, XRD indicated the solid to be composed of whitlockite plushydroxyapatite. Heated to 300° C., 2 hours (Major) Calcium pyrophosphate[Ca₂P₂O₇] (minor) Octacalcium phosphate [Ca₄H(PO₄)₃.2H₂O] Heated to 500°C., 1 hour (Major) Whitlockite [b-Ca₃(PO₄)₂] (minor) HAp [Ca₅(PO₄)₃(OH)]

Example 5 Low Temperature Calcium Phosphate Powder

[0204] Example 1 was repeated with the addition of 10.00 g dicalciumphosphate dihydrate, DCPD, CaHPO4.2H₂O (Aldrich Chemical Co., Inc.#30,765-3, CAS #7789-77-7) to the homogeneous solution followingendothermic dissolution of the calcium nitrate salt. The DCPD waspresent both as suspended solids and as precipitated material (noagitation used). Warming of the sample to >25° C. initiated anexothermic reaction as described in Example 1, resulting in theformation of a white, pasty solid. Heat treatment and X-ray diffractionof this solid were conducted as described in Example 1. Following heattreatment in air at 500° C. for 1 hour, XRD indicated the solid to becomposed of whitlockite as the primary phase along with calciumpyrophosphate (Ca₂P₂O₇) as the secondary phase. Heated to 500° C., 1hour (Major) Whitlockite [β-Ca₃(PO₄)₂] (minor) Ca₂P₂O₇

Example 6 Low Temperature Zinc Phosphate Powder Preparation

[0205] An aqueous solution of 8.51 g 50 wt % H₃PO₂ in 8.00 g distilledwater was prepared as described in Example 1. To this solution was added28.78 g zinc nitrate hexahydrate salt, Zn(NO₃)₂.6H₂O (ACS reagent,Aldrich Chemical Co., Inc. #22,873-7, CAS #10196-18-6), equivalent to21.97 wt % Zn. The molar ratio of Zn/phosphate in this mixture was 3/2and the equivalent solids level [as Zn₃(PO₄)₂] was 27.5 wt %.Endothermic dissolution of the zinc nitrate hexahydrate proceeded givinga homogeneous solution once the sample warmed to room temperature.Further warming of this solution to >25° C. on a hotplate initiated areaction in which the solution vigorously evolved red-brown acrid fumesof NO_(x(g)). The reaction continued for approximately 10 minutes whilethe sample remained a clear, colorless solution, abated somewhat for aperiod of five minutes, then vigorously resumed finally resulting in theformation of a mass of moist white solid, some of which was veryadherent to the walls of the Pyrex beaker used as a reaction vessel. Thehot solid was allowed to cool to room temperature and was stored in apolyethylene vial.

[0206] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 1 hour, XRD indicated the solid to be composed of Zn₃(PO₄)₂ (PDF30-1490).

[0207] Heated to 500° C., 1 hour (Major) Zn₃(PO₄)₂

Example 7 Low Temperature Iron Phosphate Powders

[0208] An aqueous solution of 17.50 g 50 wt % H₃PO₂ was combined with15.00 g distilled water to form a clear, colorless solution contained ina 250 ml Pyrex beaker on a hotplate/stirrer. To this solution was added53.59 g ferric nitrate nonahydrate salt, Fe(NO₃)₃-9H₂O (ACS reagent,Alfa/Aesar reagent #33315, CAS #7782-61-8), equivalen to 13.82 wt % Fe.The molar ratio of Fe/phosphate in this mixture was 1/1 and theequivalent solids level [as FePO₄] was 23.2 wt %. Endothermicdissolution of the ferric nitrate nonahydrate salt proceeded partiallywith gradual warming of the reaction mixture, eventually forming a palelavender solution plus undissolved salt. At some temperature >25° C., anexothermic reaction was initiated which evolved NO_(x(g)). This reactioncontinued for approximately 15 minutes during which time the reactionmixture became syrup-like in viscosity. With continued reaction, somepale yellow solid began to form at the bottom of the beaker. Afterapproximately 40 minutes of reaction, the sample was allowed to cool toroom temperature. The product consisted of an inhomogeneous mixture oflow density yellow solid at the top of the beaker, a brown liquid withthe consistency of caramel at the center of the product mass, and a sandcolored solid at the bottom of the beaker. The solids were collected asseparate samples insofar as was possible.

[0209] Heat treatment and X-ray diffraction of the solid collected fromthe top of the beaker were conducted as described in Example 1.Following heat treatment in air at 500° C. for 1 hour, XRD indicated thesolid to be composed of graftonite [Fe₃(PO₄)₂] (PDF 27-0250)-plus someamorphous material, suggesting that the heat treatment was notsufficient to induce complete sample crystallization as illustratedbelow:

[0210] Heated to 500° C., 1 hour (Major) Graftonite [Fe₃(PO₄)₂]

[0211] Some mechanism apparently occurs by which Fe³⁺ was reduced toFe²⁺.

Example 8 Low Temperature Calcium Phosphate Powders

[0212] An aqueous solution of 19.41 g 50 wt % H₃PO₂ was combined with5.00 g distilled water to form a clear, colorless solution contained ina 250 ml Pyrex beaker. To this solution was added 34.72 g Ca(NO₃)₂.4H₂O.The molar ratio of Ca/phosphate in this mixture was 1/1 and theequivalent solids level [as CaHPO₄] was 33.8 wt %. Endothermicdissolution of the calcium nitrate tetrahydrate proceeded under ambienttemperature conditions, eventually forming a homogeneous solution oncethe sample warmed to room temperature. Warming of this solution above25° C. initiated a vigorous exothermic reaction which resulted in theevolution of NO_(x(g)), rapid temperature increase of the sampleto >100° C., and extensive foaming of the reaction mixture over thebeaker rim, presumably due to flash boiling of water at the highreaction temperature. After cooling to room temperature, the reactionproduct was collected as a dry, white foam which was consolidated bycrushing to a powder.

[0213] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Results are as follows: Heated to 300° C., 2hours (Major) Ca₂P₂O₇ (minor) Octacalcium phosphate [Ca₄H(PO₄)₃—2H₂O]Heated to 500° C., 1 hour (Major) Ca₂P₂O₇

Example 9 Low Temperature Calcium Phosphate Powders

[0214] Example 3 was repeated using ten times the indicated weights ofreagents. The reactants were contained in a 5½″ diameter Pyrexcrystallizing dish on a hotplate/stirrer. The reactants were stirredcontinuously during the dissolution and reaction stages. The chemicalreaction initiated by heating the solution to >25° C. resulted in theevolution of NO_(x(g)) for several minutes with no apparent effect onthe stability of the system, i.e. the solution remained clear andcolorless with no evidence of solid formation. After abating for severalminutes, the reaction resumed with increased intensity resulting in thevoluminous generation of NO_(x(g)) and the rapid appearance of a pastywhite solid material. The reaction vessel and product were both hot fromthe reaction exotherm. The product was cooled in air to a white crumblysolid which was stored in a polyethylene vial.

[0215] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for either 0.5 or 1 hour, XRD indicated the solid to be composed ofwhitlockite as the primary phase along with hydroxyapatite as thesecondary phase. XRD results indicate that the relative ratio of the twocalcium phosphate phases was dependent on the duration of the heattreatment, but no attempts were made to quantify the dependence. Heatedto 500° C., 1 hour (Major) Whitlockite [b-Ca₃(PO₄)₂] (minor)Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH)

Example 10 Low Temperature Aluminum Phosphate Powders

[0216] An aqueous solution of 10.82 g 50 wt % H₃PO₂ was combined with2.00 g distilled water to form a clear, colorless solution contained ina 250 ml Pyrex beaker. To this solution was added 30.78 g aluminumnitrate nonahydrate salt, AI(NO₃)₃.9H₂O (ACS reagent, Alfa/Aesar reagent#36291, CAS #7784-27-2), equivalent to 7.19 wt % Al. The molar ratio ofAl/phosphate in this mixture was 1/1 and the equivalent solids level [asAIPO₄] was 22.9 wt %. Endothermic dissolution of the aluminum nitratenonahydrate proceeded giving a homogeneous solution once the samplewarmed to room temperature. Further waeninng of this solution to >25° C.on a hotplate initiated a reaction in which the solution vigorouslyevolved red-brown acrid fumes of NO_(x(g)). Reaction continued forapproximately 15 minutes during which the solution viscosity increasedconsiderably prior to formation of a white solid.

[0217] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 0.5 hour, XRD analysis indicated the solid to be composed of AIPO₄(PDF 11-0500) plus some amorphous material, suggesting that the heattreatment was not sufficient to induce complete sample crystallization.

Example 11 Low Temperature Calcium Phosphate Powders

[0218] An aqueous solution of 8.06 g 50 wt % H₃PO₂ reagent was combinedwith 6.00 g distilled water to form a clear, colorless solution in a 250ml Pyrex beaker on a hotplate/stirrer. To this solution was added 19.23g Ca(NO₃)₂.4H₂O. The molar ratio of Ca/phosphate in this sample was 4/3and the equivalent solids [as octacalcium phosphate, Ca₈H₂(PO₄)₆-5H₂O]was 30.0 wt %. Endothermic dissolution of the calcium nitratetetrahydrate proceeded under ambient conditions, eventually forming ahomogeneous solution once the sample warmed to room temperature. Warmingof the solution above 25° C. initiated a vigorous exothermic reaction asdescribed in Example 1. After approximately three minutes, the reactionwas essentially complete leaving a moist, white, pasty solid.

[0219] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 0.5 hour, XRD indicated the solid to be composed of whitlockite asthe primary phase along with hydroxyapatite as the secondary phase.There was no evidence for the formation of octacalcium phosphate (OCP),despite the initial sample stoichiometry. This result suggests that (a)alternate heat treatments are necessary to crystallize OCP and/or (b)excess Ca is present in the intermediate powder. Heated to 500° C., 0.5hour (Major) Whitlockite [b-Ca₃(PO₄)₂] (minor) HAp Ca₅(PO₄)₃(OH)

Example 12 Low Temperature Calcium Phosphate Powders

[0220] Example 11 was repeated except that no distilled water was usedin preparation of the reaction mixture. Warming of the homogeneoussolution above 25° C. initiated an exothermic reaction as described inExample 11. After approximately three minutes, the reaction wasessentially complete leaving a moist, pasty, white solid.

[0221] Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 0.5 hour, XRD indicated the solid to be composed of calciumpyrophosphate (Ca₂P₂O₇).

[0222] Heated to 500° C., 0.5 hour (Major) Ca₂P₂O₇

Example 13 Low Temperature Hydrothermal (HYPR) Calcium Phosphates

[0223] An aqueous solution of 50 wt % calcium nitrate tetrahydrate,Ca(NO₃)₂-4H₂O (ACS reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS#13477-34-4) was prepared by dissolving 250.0 g of the salt in 250.0 gdistilled water. This solution was equivalent to 8.49 wt % Ca. A totalof 47.0 g of this solution was added, with rapid agitation, to anaqueous solution of 50 wt % sodium hypophosphite monohydrate,NaH₂PO₂—H₂O (Alfa/Aesar reagent #14104, CAS #10039-56-2) also preparedby dissolving 250.0 g of the salt in 250.0 g distilled water. The sodiumhypophosphite solution was equivalent to 44.80 wt % [PO₄]⁻³. The clear,colorless solution of calcium nitrate and sodium hypophosphite was thendiluted with 40.3 g distilled water. The molar ratio of Ca/phosphate inthis mixture was 5/3, and the equivalent solids level [as Ca₅(PO₄)₃(OH)(hydroxyapatite)] was 10.0 wt %. The sample was hydrothermally treatedusing a 300 cc volume stirred high pressure bench reactor (Model no.4561 Mini Reactor, Parr Instrument Co., Moline, Ill. 61265) equippedwith a temperature controller/digital tachometer unit (Model no. 4842,Parr Instrument Co.) and dial pressure gauge. All wetted parts of thereactor were fabricated from type 316 stainless steel. Ordinarily, type316SS is not the material of choice for inorganic acid systems such asthe solution precursors used in this invention, since phosphoric acidcan attack stainless steel at elevated temperatures and pressures.However, in the practice of this invention, direct contact (i.e.wetting) of the reactor surfaces was avoided through the use of a Pyrexglass liner. Only the stirrer and thermocouple sheath were immersed inthe reactant solutions and no corrosion was observed. In addition, it isassumed that the high nitrate ion concentration in the reactant mixtureprovided a passivating environment for the type 316SS.

[0224] One hundred grams (approximately 100 ml) of the calciumnitrate—sodium hypophosphite solution was placed in the Pyrex liner ofthe reactor and the intervening space between the glass liner and thereactor vessel was filled with distilled water to the level of thesample. This ensured maximum heat transfer to the sample since thereactor was externally heated by an electric mantle. The approx. 100 mlsample volume left sufficient head space in the reactor to accommodatesolution expansion at elevated temperatures. The reactor was sealed bycompression of a Teflon gasket. Heating of the reactor was performed atthe maximum rate of the controller to a set point of 202° C. withconstant stirring (500 r.p.m.). The heating profile, as monitored by athermocouple increased in the reactant mixture, was as follows: REACTORTHERMAL PROFILE Time (min) 0 5 10 15 20 25 30 35 36 Temp. 22 49 103 122145 155 179 197 200 (° C.) (hold) (+/− 2° C.) Pressure — — — — — 160 210220 (psi)

[0225] After holding at 200+/−3° C. for 12 minutes, the temperaturerapidly increased to 216° C. with a resultant increase in reactorpressure to approximately 330 psi. This exothermic event quicklysubsided as evidenced by the rapid drop in reactor temperature to 208°C. within two minutes as the Parr reactor approached thermal equilibriumvia a near-adiabatic process. After 15 minutes at 200° C., the reactorwas removed from the heating mantle, quenched in a cold water bath, andopened after the head space was vented to ambient pressure.

[0226] A white precipitate was present in the glass liner. The solid wascollected by vacuum filtration on a 0.45 micron membrane filter(Millipore, Inc., Bedford, Mass., 01730), washed several times withdistilled water, and dried at approximately 55° C. in a forcedconvection oven. X-ray diffraction of this solid was conducted asdescribed in Example 1.

[0227] X-Ray diffraction results indicate a unique, unidentifiablediffraction pattern.

Example 14 Low Temperature Hydrothermal (HYPR) Calcium Phosphate Powders

[0228] Example 13 was repeated except that 40.3 g of 1.0 M NaOH solutionwas added with rapid stirring to the homogeneous solution of calciumnitrate and sodium hypophosphite instead of the distilled water. Thisbase addition resulted in the formation of a milk white dispersion,presumably due to precipitation of Ca(OH)₂.

[0229] The sample was hydrothermally processed as described in Example13 with the temperature set point at 207° C. The temperature ramp to160° C. (25 minutes) was as indicated for Example 13. At 30 minutes intothe run, an exotherm occurred causing the temperature of the reactionmixture to rise to a maximum of 221° C. within five minutes with acorresponding pressure increase to 370 psi. At 38 minutes into theexperiment, the reactor was quenched to room temperature.

[0230] The reaction product consisted of a small amount of whiteprecipitate. The material was collected as described in Example 13.X-ray diffraction of the dried sample was conducted as described inExample 1. XRD results indicated the solid to be comprised of the sameunidentifiable pattern (crystal phase) found in Example 13 and minoramounts of HAp—[Ca₅(PO₄)₃(OH)].

Example 15 Low Temperature Hydrothermal (HYPR) Calcium Phosphate Powders

[0231] A total of 47.0 g of a 50 wt % aqueous solution of calciumnitrate tetrahydrate was diluted with 53.0 g distilled water. Then, 6.00g calcium hypophosphite salt, Ca(H₂PO₂)₂ (Alfa/Aesar reagent #56168, CAS#7789-79-9), equivalent to 23.57 wt % Ca and 111.7 wt % [PO4]⁻³, wasslurried into the Ca(NO₃)₂ solution using rapid agitation. An unknownamount of the calcium hypophosphite remained undissolved in the roomtemperature sample. The solubility behavior of Ca(H₂PO₂)₂ in theCa(NO₃)₂ solution at elevated temperatures is unknown. The molar ratioof Ca/phosphate in this system was 1.91.

[0232] This sample was hydrothermally processed as described in Example13 with the temperature set point at 212° C. The temperature ramp to200° C. was as indicated for Example 13. At 39 minutes into the run, anexotherm occurred causing the temperature of the reaction mixture torise to a maximum of 252° C. within three minutes with a correspondingpressure increase to 640 psi. At 44 minutes into the experiment, thereactor was quenched to room temperature.

[0233] The reaction product appeared as a voluminous white precipitateplus some suspended solids. The material was collected as described inExample 13. X-ray diffraction of the dried solid was conducted asdescribed in Example 1. XRD showed the major peak at position 30.2°(2-theta) which indicated the solid to be monetite, CaHPO₄. The uniquecrystal morphology is depicted in the scanning electron micrographrepresentation in FIG. 2.

[0234] Mixtures of the above described RPR and HYPR powders are usefulin the formation of self-setting calcium phosphate cements for therepair of dental and orthopaedic defects. The addition of specificcomponents and solubilizing liquids can also be added to form theprecursor bone mineral constructs of this invention.

Example 16 Cement Compositions

[0235] Approximately 1.4 g of an alkaline solution (7 molar) formedusing NaOH and distilled water, was mixed with 1.1 g of HYPR monetite[Example 15] and 1.1 g of RPR β-TCP-HAp(CO₃) [Example 3] in a glassmortar and pestle for ˜45 seconds. After mixing, a smooth paste wasformed, which was scooped into a 3 ml polypropylene syringe and sealedfor 20 minutes without being disturbed. Room temperature setting wasobserved after 20 minutes, which was indicated by the use of a 454 gramGilmore needle. The hardened cement analyzed by X-ray diffraction showedpeaks which revealed a conversion to primarily type-B. carbonatedapatite which is the desired bone mineral precursor phase: Cement XRDrevealed (Major) Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH) (minor) Whitlockite[b-Ca₃(PO₄)₂]

Example 17 Cement Compositions

[0236] A stock solution was formed with the approximately 7 M NaOHsolution used in Example 1 and 1.0% polyacrylic acid (PAA). PAA is usedas a chelating setting additive and wetting agent. The above solutionwas used with several powder combinations to form setting cements. A50/50 powder mix of HYPR monetite [Example 15] and RPR β-TCP-HAp(CO₃)[Example 3], approximately 0.7 g, was mixed with a glass spatula on aglass plate with 0.39 g of the 1% PAA-NaOH solution (powder to liquidratio=1.73). The cement was extruded through a 3 ml syringe and was setafter being left undisturbed for 20 minutes at room temperature (23°C.).

Example 18-34

[0237] Examples 18-34: Set Time Powder/ (min.) Powder/ Gilmore NeedleLiquid ratio (454 grams) Example Powder Liquid (Consistency) # = (1200grams) 18 HYPR monetite + 7M NaOH 1/1/1.2   <20 min (#) RPR (Ex. 1)Alkaline Sol'n (slightly wet RPR (Ex. 1) paste) 19 HYPR monetite 7M NaOH1/1/1.2   <20 min (#) (Ex. 15) + Alkaline Sol'n (wet paste) RPR (Ex. 1)700° C. 20 HYPR monetite 7M NaOH 1/1/1     15-18 min (Ex. 15) + AlkalineSol'n (sl. wet paste) −50 μm 45S5^(#) glass 21 RPR (Ex. 1) 7M NaOH 1.5/1  >40 min 500° C. Alkaline Sol'n (wet paste) ‘neat’ 22 RPR (Ex. 1) 7MNaOH 1.7/1     40 min 300° C. + Alkaline Sol'n (sl. wet paste) RPR (Ex.9) 500° C. 23 HYPR monetite 7M NaOH 1/1/1.4 No Set up to (Ex. 15) +Alkaline Sol'n (v. gritty, wet) 24 hrs. Commercial β- TCP 24 HYPRmonetite 7M NaOH 1/1/1.4     20 min (#) (Ex. 15) + Alkaline Sol'n(slightly wet RPR (Ex. 2) paste) 500° C. 25 HYPR monetite 7M NaOH 1/1/1  <30 min (Ex. 15) + Alk. Sol'n + (claylike sl. set RPR (Ex. 2) 20% PAApaste) 500° C. 26 HYPR monetite 7M NaOH 1/1/1     35 min (Ex. 15) + Alk.Sol'n + (claylike RPR (Ex. 2) 5% PAA paste) 500° C. 27 HYPR monetite 7MNaOH 1/1/1.2     12-15 min (Ex. 15) + Alk. Sol'n + (slightly dry RPR 1%PAA paste) (Ex. 11) 500° C. 28 HYPR monetite 10 wt % 1/1/1.2      1 hr15 min (Ex. 15) + Ca(H₂PO₂)₂ (very wet RPR (Ex. 1) (aq) paste) 500° C.29 RPR 10 wt % 1.7/1     45 min (Ex. 11) 500° C. Ca(H₂PO₂)₂ (very wetpaste) ‘neat’ (aq) 30 RPR 10 wt % 2.5/1     20 min (Ex. 11) 500° C.Ca(H₂PO₂)₂ (sl. dry ‘neat’ (aq) paste/putty) 31 RPR 10 wt % 2.25/1    15 min (Ex. 11) 500° C. Ca(H₂PO₂)₂ + (very good ‘neat’ 1 wt %paste/putty) H₂PO₂ (aq) 32 HYPR monetite 3.5 M NaOH 1/1/1     35 min.(Ex. 15) + Alk. Sol'n. (good RPR paste/putty) * 12 min. (Ex. 11) 500° C.33 HYPR monetite 3.5 M NaOH 1/3/2     38 min. (Ex. 15) + Alk. Sol'n.(paste/putty) RPR * 15 min. (Ex. 11) 500° C. 34 HYPR monetite Saline,EDTA 1/1/1     43 min. (Ex. 15) + buffered (good RPR paste/putty) * 20min. (Ex. 11) 500° C.

Example 35 Low Temperature Neodymium Phosphate Powders

[0238] An aqueous solution of 11.04 g of 50 wt. % H₃PO₂ was diluted with5.00 g distilled water to form a clear, colorless solution contained ina 250 ml fluoropolymer resin beaker on a hotplate/magnetic stirrer.Added to this solution was 36.66 g neodymium nitrate hexahydrate salt,Nd(NO₃)₃-6H₂O (Alfa/Aesar reagent #12912, CAS # 16454-60-7), equivalentto 32.90 wt % Nd. The molar ratio of the Nd/P in this mixture was 1/1and the equivalent solids level (as NdPO₄) was 38.0 wt. %. Endothermicdissolution of the neodymium nitrate hexahydrate salt proceeded withgradual warming of the reaction mixture, eventually forming a clear,homogeneous lavender solution at room temperature. Heating of thissolution with constant agitation to approximately 70° C. initiated avigorous endothermic reaction which resulted in the evolution ofNO_(x(g)), rapid temperature increase of the sample to approximately100° C., and finally, formation of a pasty lavender mass. Heat treatmentof the pasty solid and subsequent X-ray diffraction analysis of thefired solid were conducted as described in Example 1. Results of theanalysis are as follows: Heated to 500° C., 45 minutes (Major) Neodymiumphosphate hydrate [NdPO₄—0.5H₂O] (PDF 34-0535) Heated to 700° C., 45minutes (Major) Monazite-Nd [NdPO₄] (PDF 46-1328)

Example 36 Low Temperature Cerium Phosphate Powders

[0239] An aqueous solution of 11.23 g of 50 wt. % H₃PO₂ was diluted with5.00 g distilled water to form a clear, colorless solution contained ina 250 ml fluoropolymer resin beaker on a hotplate/magnetic stirrer.Added to this solution was 36.94 g cerium nitrate hexahydrate salt,Ce(NO₃)₃-6H₂O (Johnson-Matthey reagent #11329-36), equivalent to 32.27wt % Ce. The molar ratio of the Ce/P in this mixture was 1/1 and theequivalent solids level (as CePO₄) was 37.6 wt %. Endothermicdissolution of the neodymium nitrate hexahydrate salt proceeded withgradual warming of the reaction mixture, eventually forming a clear,homogeneous colorless solution at room temperature. Heating of thissolution with constant agitation to approximately 65° C. initiated avigorous endothermic reaction which resulted in the evolution ofNO_(x(g)), rapid temperature increase of the sample toapproximately >100° C., and finally, formation of a pasty light greymass. Heat treatment of the pasty solid and subsequent X-ray diffractionanalysis of the fired solid were conducted as described in Example 1.Results of the XRD analysis are as follows:

[0240] Heated to 700° C., 45 minutes (Major) Monazite-Ce [CePO₄] (PDF32-0199)

Example 37 Low Temperature Yttrium Phosphate, Powders

[0241] An aqueous solution of 14.36 g of 50 wt. % H₃PO₂ was diluted with5.00 g distilled water to form a clear, colorless solution contained ina 250 ml fluoropolymer resin beaker on a hotplate/magnetic stirrer.Added to this solution was 41.66 g yttrium nitrate hexahydrate salt,Y(NO₃)₃-6H₂O (Alfa/Aesar reagent #12898, CAS # 13494-98-9), equivalentto 23.21 wt % Y. The molar ratio of the YIP in this mixture was 1/1 andthe equivalent solids level (as YPO4) was 32.8 wt %. Endothermicdissolution of the yttrium nitrate hexahydrate salt proceeded withgradual warming of the reaction mixture, eventually forming a clear,homogeneous colorless solution at room temperature. Heating of thissolution with constant agitation to approximately 75° C. initiated avigorous endothermic reaction which resulted in the evolution ofNO_(x(g)), rapid temperature increase of the sample toapproximately >100° C., and finally, formation of a pasty white mass.Heat treatment of the pasty solid and subsequent X-ray diffractionanalysis of the fired solid were conducted as described in Example 1.Results of the XRD analysis are as follows:

[0242] Heated to 700° C., 45 minutes (Major) Xenotime [YPO₄] (PDF11-0254)

Example 38 Broad Applicabililty

[0243] A wide variety of minerals can be made in accordance with thepresent invention. In the following two tables, oxidizing and reducingagents are listed. Any of the listed oxidants can be reacted with any ofthe listed reducing agents and, indeed, blends of each may be employed.Appropriate stoichiometry will be employed such that the aforementionedreaction is caused to proceed. Also specified are possible additives andfillers to the reactions. The expected products are given as are some ofthe expected fields of application for the products. All of thefollowing are expected generally to follow the methodology of some orall of the foregoing Examples. Oxidizing Agents Reducing AgentsAdditives Product(s) Compounds of the form Oxoacids of Group 5B, 6B, andAl₂O₃, ZrO₂, TiO₂, SiO₂, Ca(OH)₂, XY(PO₄), XY(SO₄), XNO₃, where X = 7B,(where 5B includes N, P, DCPD, DCPA, HAp, TCP, TTCP, XY(PO₄)(SO₄), H,Li, Na, K, Rb, Cs, and As; 6B includes S, Se, and MCMP, ZrSiO₄, W-metal,Fe metal, Ti WXYZ(PO₄)(SO₄)(CO₃), Cu, Ag, and Hg. Te; 7B includes Cl,Br, and I). metal, Carbon black, C-fiber or flake, WXYZ(PO₄(SO₄)(CO₃)(F,Cl, Br, I), CaF₂, NaF, carbides, nitrides, glass WXYZ(PO₄)(SO₄)Compounds of the form Phosphorous oxoacid fibers, glass particulate,glass-ceramics, (CO₃)(F, Cl, Br, I)(OCl, OF, OBr, X(NO₃)₂, where X = Be,compounds: alumina fibers, ceramic fibers, OI), in the form of fiber,flake, Mg, Ca, Sr. Ba, Cr, Mn, Hypophosphite (H₃PO₂); bioactive ceramicfibers and whisker, granule, coatings, Fe, Co, Ni, Cu, Zn, Rh,Hypophosphoric acid (H₄P₂O₆); particulates, polyacrylic acid, polyvinylagglomerates and fine powders. Pd, Cd, Sn, Hg, and Pb Isohypophosphoricacid alcohol, polymethyl-methacrylate, (H₄P₂O₆); polycarbonate, andother stable Phosphonic acid or phosphorus polymeric compounds. acid(H₃PO₃); Acetates, formates, lactates, simple Diphosphonic acid(H₄P₂O₅); carboxylates, and simple sugars. Phosphinic acid orhypophosphorous acid (H₃PO₂). Compounds of the form Sulfur oxoacidcompounds: X(NO₃)₃ or XO(NO₃), Thiosulfuric acid (H₂S₂O₃); where X = Al,Cr, Mn, Dithionic acid (H₂S₂O₆); Fe, Co, Ni, Ga, As, Y, Polythionic acid(H₂S_(n+2)O₆); Nb, Rh, In, La, Tl, Bi, Sulfurous acid (H₂SO₃); Ac, Ce,Pr, Nd, Steven Disulfurous acid (H₂S₂O₅); Meyer, Eu, Gd, Tb, Dy,Dithionous acid (H₂S₂O₄). Ho, Er, Tm, Yb, Lu, U, and Pu Compounds of theform X(NO₃)₄ or XO(NO₃)₂, where X = Mn, Sn, Pd, Zr, Pb, Ce, Pr, Tb, Th,Pa, U and Pu. Halogen oxoacids: perhalic acid (HOClO₃, HOBrO₃, HOIO₃);halic acid (HOClO₂, HOBrO₂, HOIO₂); halous acid (HOClO, HOBrO, HOIO)

[0244] The minerals prepared above may be used in a wide variety ofapplications. Examples of these applications may include, but are notlimited to, use as pigments, phosphors, fluorescing agents, paintadditives, synthetic gems, chromatography media, gas scrubber media,filtration media, bioseparation media, zeolites, catalysts, catalyticsupports, ceramics, glasses, glass-ceramics, cements, electronicceramics, piezoelectric ceramics, bioceramics, roofing granules,protective coatings, barnacle retardant coating, waste solidification,nuclear waste solidification, abrasives, polishing agents, polishingpastes, radiopharmaceuticals, medical imaging and diagnostics agents,drug delivery, excipients, tabletting excipients, bioactive dental andorthopaedic materials and bioactive coatings, composite fillers,composite additives, viscosity adjustment additives, paper finishingadditives, optical coatings, glass coatings, optical filters,fertilizers, soil nutrient(s) additives.

Example 39 Porous Shaped Bodies of Calcium Phosphates

[0245] An aqueous solution of 17.02 g 50 wt % hypophosphorous acid,H₃PO₂ (Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95wt % [PO4]⁻³ was combined with 5.00 g deionized water to form a clear,colorless solution contained in a 250 ml Pyrex beaker. To this solutionwas added 45.70 g calcium nitrate tetrahydrate salt, Ca(NO₃)₂.4H₂O (ACSreagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4),equivalent to 16.97 wt % Ca. The molar ratio of [Ca]²⁺/[PO₄]⁻³ in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 29.53wt %. Endothermic dissolution of the calcium nitrate tetrahydrateproceeded under ambient temperature conditions, eventually forming ahomogeneous solution. The viscosity of this solution was water-like,despite the high salt concentration.

[0246] A piece of damp (as removed from the packaging) cellulose sponge(O-Cel-O™, 3M Home and Commercial Care Division, P.O. Box 33068, St.Paul. Minn. 55133), trimmed to a block approximately 1.5″×1.5″×2.0″, wasimmersed in the calcium nitrate+hypophosphorous acid solution andkneaded (alternately compressed and decompressed) to fully imbibe thereactant solution into the sponge. The approximately 4.5 cubic inchsponge block (approximately 3.5 g), thoroughly saturated with reactantsolution (liquid uptake approximately 7 to 8 times the virgin spongeweight), was placed on a platinum plate in a laboratory furnace (Vulcanmodel 3-550, NEYTECH, Inc., 1280 Blue Hills Ave., Bloomfield, Conn.06002) that was preheated to 500° C. After several seconds, a reactioncommenced at the surface of the sponge with the evolution of red-brownfumes characteristic of NO_(x(g)). As the reaction proceeded from thesurface to the interior of the sponge block, NO_(x(g)) evolutioncontinued and some reactant liquid exuded from the sponge andaccumulated at the bottom of the Pt plate as a crusty white mass ofsolid. The cellulose sponge itself was consumed as the reactionprogressed and the reactant mass attained the oven temperature. Afterthermal treatment at 500° C. for 45 minutes, the sample was removed fromthe lab furnace. The sample had been converted to an inorganic replicaof the original organic sponge structure. The vestigial structurerepresented a positive version of the original sponge structure withfaithful replication of the cellular elements, porosity, andmacrostructure. The vestigial mass was mottled gray suggesting thepresence of some residual carbon in the structure due to incompleteburnout of the combustion products from the cellulose sponge matrix. Thevestigial mass was fragile with very low apparent density, but it wasrobust enough to be handled as a coherent block of highly porous solidonce it was removed from the exudate material.

[0247] An X-ray diffraction (XRD) pattern was obtained from a packedpowder sample of the inorganic sponge material pulverized in a mortarand pestle. The pattern was obtained using a Pigaku MiniFlex instrument(Rigaku/USA, Inc., Northwoods Business Park, 199 Rosewood Dr., Danvers,Mass. 01923) running JADE pattern processing software (Materials Data,Inc., P.O. Box 791, Livermore, Calif. 94551) using a 2 degree/minutescan rate over the 2 theta angular range from 15-50°. The XRD patternfor this material is shown in FIG. 11. Peak analysis indicated the solidto consist of whitlockite Ca₃(PO₄)₂ (PDF 09-0169) and hydroxyapatiteCa₅(PO₄)₃(OH) (PDF 09-0432).

[0248] A sample of the O-Cel-O™ cellulose sponge was prepared forscanning electron microscopy by sputter coating with Pt using a Hummer6.2 Sputtering System (Anatech, Inc., 6621-F Electronic Drive,Springfield, Va. 22151). SEM examination was performed using a JEOLmodel JSM-840A microscope (JEOL USA, Inc., 11 Dearborn Road, P.O. Box6043, Peabody, Mass. 01961). FIG. 12 shows a SEM image of the virgincellulose sponge. FIG. 13 shows a SEM image of the calcium phosphatematerial prepared from the cellulose sponge.

Example 40 Transformed Shaped Bodies of Calcium Phosphate

[0249] The material from Example 39 was fired under a variety ofconditions in order to (1) eliminate residual carbon from the structureand (2) attempt to promote sintering reactions in order to strengthenthe inorganic sponge matrix. The samples were fired on Pt plates in aLindberg model 51333 box furnace (Lindberg/Blue M, Inc., 304 Hart St.,Watertown, Wis. 53094) equipped with a Lindberg series 59000 controlconsole. The following table summarizes these results: Temp./timeObservations XRD  900° C. 15 minutes Snow white mass 1000° C. 1 hourSnow white mass 1100° C. 1 hour Snow white mass 1100° C. 13 hours Snowwhite mass Whitlockite (FIG. 14) 1200° C. 13 hours Snow white mass 1350°C. 1 hour Snow white mass Whitlockite (FIG. 15)

[0250] A subjective assessment of the strength of these heat treatedspecimens showed no apparent changes. There was no indication thatsintering occurred even at temperatures up to 1350° C.

Example 41 Shaped Bodies

[0251] A solution was prepared as described in Example 39 using 9.70 g50 wt % H₃PO₂, no deionized water, and 17.38 g Ca(NO₃)₂4H₂O to obtain amolar ratio of [Ca]²⁺[PO₄]⁻³ of 1.0 and an equivalent solids level [asCaHPO₄] of 36.92 wt %. A block,of damp O-Cel-O™ sponge (as removed fromthe packaging) was fully imbibed with the reactant solution, set in aporcelain crucible, and placed into a Vulcan lab oven preheated to 500°C. After 1 hour at 500° C., the mottled gray sample was refired at 800°C. (Vulcan furnace) for 15 minutes. The final inorganic sponge samplewas completely white indicating complete carbon burnout. An XRD pattern(FIG. 16) was obtained from a packed powder sample prepared as describedin Example 39. Peak analysis indicated the solid to consist of calciumpyrophosphate, Ca₂P₂O₇ (PDF 33-0297).

Example 42 Shaped Bodies of Zinc Phosphate

[0252] An aqueous solution of 13.67 g 50 wt % H₃PO₂ was combined with5.00 g deionized water to form a clear, colorless solution contained ina 250 ml Pyrex beaker. To this solution was added 46.23 g zinc nitratehexahydrate salt, Zn(NO₃)₂6H₂O (Aldrich Chemical Co., Inc. #22,873-7,CAS #10196-18-6), equivalent to 21.97 wt. % Zn. The molar ratio of[Zn]²⁺/[PO₄]⁻³ in this mixture was 3/2 and the equivalent solids level[as Zn₃(PO₄)₂] was 27.5 wt. %.

[0253] Endothermic dissolution of the zinc nitrate hexahydrate proceededunder ambient temperature conditions, eventually forming a homogeneoussolution. A block of O-Cel-O™ sponge was fully imbibed with thisreactant solution as described in Example 39. The sample was first firedat 500° C. for 1 hour and then at 800° C. for 15 minutes. The inorganicsponge sample was light gray in color (due to residual carbon) and itwas robust enough to be handled as a coherent block of low density,highly porous material. An XRD pattern (FIG. 17) was obtained from apacked powder sample prepared as described in Example 39. Peak analysisindicated the solid to consist of zinc phosphate, Zn₃(PO₄)₂ (PDF30-1490).

Example 43 Neodymnium Phosphate Bodies

[0254] An aqueous solution of 11.04 g 50 wt % H₃PO₂ was combined with5.00 g deionized water to form a clear, colorless solution contained ina 250 ml Pyrex beaker. To this solution was added 36.64 g neodymiumnitrate hexahydrate salt, Nd(NO₃)₃.6H₂O (Alfa/Aesar reagent #12912, CAS#16454-60-7), equivalent to 32.90 wt % Nd. Endothermic dissolution ofthe neodymium nitrate hexahydrate proceeded under ambient temperatureconditions, eventually forming a pale lavender homogeneous solution. Ablock of O-Cel-O™ sponge was fully imbibed with this reactant solutionas described in Example 39. The sample was first fired at 500° C. for 1hour and then at 800° C. for 15 minutes. The inorganic sponge sample waspale lavender in color at the outside of the inorganic sponge mass andlight gray in the interior (due to residual carbon). The inorganicsponge mass was very fragile, but it was robust enough to be handled asa coherent block of low density, highly porous material. An XRD pattern(FIG. 18) was obtained from a. packed powder sample prepared asdescribed in Example 39. Peak analysis indicated the solid to consist ofneodymium phosphate, NdPO₄ (PDF 25-1065).

Example 44 Aluminium Phosphate Bodies

[0255] An aqueous solution of 21.65 g 50 wt % H₃PO₂ was combined with5.00 g deionized water to form a clear, colorless solution contained ina 250 ml Pyrex beaker. To this solution was added 61.56 g aluminumnitrate nonahydrate salt, Al(NO₃)₃.9H₂O (Alfa/Aesar reagent #36291, CAS#7784-27-2), equivalent to 7.19 wt. % Al. Endothermic dissolution of thealuminum nitrate hexahydrate proceeded under ambient temperatureconditions, eventually forming a homogeneous solution. A block ofO-Cel-O™ sponge was fully imbibed with this reactant solution asdescribed in Example 39. The sample was first fired at 500° C. for 1hour and then at 800° C. for 15 minutes. The inorganic sponge sample waswhite at the outside of the inorganic sponge mass and light gray in theinterior (due to residual carbon). The inorganic sponge mass could behandled as a coherent block of low density, highly porous material. AnXRD pattern (FIG. 19) was obtained from a packed powder sample preparedas described in Example 39. Peak analysis indicated the solid to consistof aluminum phosphate, AIPO₄ (PDF 11-0500).

Example 45 Modified Porous Structures

[0256] A piece of the inorganic sponge material from Example 39 wasimmersed in molten paraffin wax (CAS #8002-74-2) (Northland Canning Wax,Conros Corp., Detroit, Mich. 48209) maintained at >80° C. so as toimbibe the porous structure. The inorganic sponge, wetted with moltenwax, was removed from the molten wax and allowed to cool at roomtemperature. The wax solidified on cooling and imparted additionalstrength and improved handling properties to the inorganic spongematerial such that the paraffin wax-treated material could be cut andshaped with a knife. Most of the formerly open porosity of the inorganicsponge material was filled with solidified paraffin wax.

Example 46 Gelatin Modification

[0257] A piece of the inorganic sponge material from Example 39 wasimmersed in a solution prepared by dissolving 7.1 g food-grade gelatin(CAS # 9000-70-0) (Knox Unflavored Gelatin, Nabisco Inc., East Hanover,N.J. 07936) in 100.0 g deionized water at approximately 90° C. Theinorganic sponge material readily imbibed the warm gelatin solution and,after several minutes, the largely intact piece of inorganic spongematerial was carefully removed from the solution and allowed to cool anddry overnight at room temperature. The gelatin solution gelled oncooling (bloom strength unknown) and imparted additional strength andimproved handling properties to the inorganic sponge material. Althoughno pH or electrolyte/nonelectrolyte concentration adjustments were madeto the system described in this example, it is anticipated that suchadjustments away from the isoelectric point of the gelatin would impartadditional rigidity to the gelatin gel and, thereby, to thegelatin-treated inorganic sponge material. Significant additionalstrength and improved handling properties were noted in thegelatin-treated inorganic sponge material after the gelatin was allowedto thoroughly dry for several days at room temperature. Some shrinkageof the gelatin-treated inorganic sponge materials was noted on drying.The shrinkage was nonuniform with the greatest contraction noted nearthe center of the body. This central region was, of course, the lastarea to dry and, as such, was surrounded by hardened inorganic spongematerial which could not readily conform to the contraction of the coreas it dehydrated. The material exhibited considerable improvement incompression strength and a dramatically reduced tendency to shedparticulate debris when cut with a knife or fine-toothed saw. It ispresumed that the film-forming tendency of the gelatin on drying inducedcompressive forces on the internal cellular elements of the inorganicsponge material, thereby strengthening the overall structure.

[0258] Cylindrical plugs could be cored from pieces of the air driedgelatin-treated inorganic sponge material using hollow punch toolsranging from ½ inch down to ⅛ inch in diameter.

[0259]FIG. 20 is a SEM of the air-dried gelatin treated inorganicsponge, which was prepared as described in Example 39. A comparison ofthis SEM with that of the initial cellulose sponge material (FIG. 12)shows how faithfully the sponge micro- and macrostructure has beenreplicated in the inorganic sponge material. FIG. 21 is a SEM of sheeptrabecular bone. The highly porous macrostructure of sheep trabecularbone is representative of the anatomical structure of cancellous bone ofhigher mammals, including humans. The sample of sheep trabecular bonewas prepared for SEM analysis by sputter coating (as described inExample 39) a cross-sectional cut from a desiccated sheep humerus. FIG.22 is a higher magnification SEM of the air-dried gelatin treatedinorganic sponge depicted in FIG. 20. From this SEM micrograph, thepresence of meso- and microporosity in the calcium phosphate matrix isreadily apparent.

Example 47 Implant Cages

[0260] A rectangular block approximately ¼ inch×½ inch×¾ inch was cutfrom a piece of damp (as removed from the packaging) O-Cel-O™ cellulosesponge. This sponge piece was trimmed as necessary so to completely fillthe internal cavity of a titanium nitride (TiN)-coated box-like spinalimplant cage (Stratech Medical, Inc.). The sponge insert wasintentionally made slightly oversized to ensure good fit and retentionin the cage assembly. The cellulose sponge block was fully imbibed witha reactant solution prepared as described in Example 39. Thesolution-saturated sponge insert was then inserted through the open sideof the spinal cage assembly and manipulated to completely fill theinterior cavity of the implant assembly. Despite the compliance of thesolution-saturated sponge, there was almost no penetration of the spongeinto the fenestrations of the implant. The sponge-filled cage assembly,sitting on a Pt plate, was placed in a laboratory oven preheated to 500°C. and held at that temperature for 1 hour. After cooling to roomtemperature, the implant assembly was removed from the small amount ofcrusty white solid resulting from reactant solution which had exudedfrom the sponge insert and coatec-the surface of the implant. The TiNcoating on the cage appeared unaffected by the treatment, and theinternal chamber was filled with inorganic sponge material having amottled gray appearance. The filled cage assembly was refired at 800° C.for 30 minutes in an attempt to eliminate residual carbon from theinorganic sponge material. After cooling, examination of the implantassembly revealed that the TiN coating had been lost via oxidation,while the inorganic sponge material was completely white. There wasexcellent retention of the inorganic sponge material in the chamber ofthe spinal cage assembly.

Example 48 Orthopaedic Implants

[0261] Two cylindrical plugs of approximately ⅜ inch diameter and ½ inchlength were cut from a piece of damp (as removed from the packaging)Marquis™ cellulose sponge (distributed by Fleming Companies, Inc.,Oklahoma City, Okla. 73126) using a hollow punch (Michigan IndustrialTools, P.O. Box 88248, Kentwood, Mich. 49518) of the appropriate size.These cellulose sponge plugs were then trimmed to the necessary lengthso to completely fill the bicomparttnental central cavity of a 13 mm×20mm (diameter×length) BAK threaded cylindrical interbody implant(SpineTech, Inc., 7375 Bush Lake Road, Minneapolis, Minn. 55439). Theplugs were intentionally made slightly oversized to ensure good fit andretention in the two chambers of the titanium spinal fusion cageassembly. The cylindrical sponge plugs were filly imbibed with areactant solution prepared as described in Example 39 and the solutionsaturated sponge plugs were inserted through the open ends of the spinalcage assembly and manipulated to completely fill both of the internalchambers of the implant assembly. Despite the compliance of thesolution-saturated sponge, there was almost no penetration of the spongeinto the fenestrations of the implant. The sponge-filled cage assemblysitting on a Pt plate was placed in a laboratory oven preheated to 200°C. Immediately, a temperature ramp to 500° C. was begun (duration of 16minutes) followed by a 30 minute hold at 500°. After cooling to roomtemperature, the implant assembly was removed from the small amount ofcrusty white solid resulting from reactant solution which had exudedfrom the sponge pieces and coated the surface of the implant. Thetitanium cage appeared unaffected by the treatment, and the chamberswere filled with inorganic sponge material having-a mottled grayappearance. The filled cage assembly was refired at 700° C. for 10minutes in an attempt to eliminate residual carbon from the inorganicsponge material. After cooling, examination of the implant assemblyrevealed that the surface of the titanium cage appeared to haveundergone some oxidation as evidenced by its roughened texture, whilethe inorganic sponge material was white at the surface but still gray atthe center of the mass. Obviously, further heat treatment would benecessary to fully oxidize the residual carbon in the interior of theinorganic sponge masses in each chamber of the implant assembly. Therewas excellent retention of the inorganic sponge material in both of thechambers of the spinal cage assembly.

Example 49 Sterilization

[0262] Samples of gelatin-treated inorganic sponge material wereprepared as described in Example 46 and allowed to thoroughly dry atroom temperature for longer than one week. Peaces of this drygelatin-treated material were subjected to prolonged oven treatments inan air atmosphere within a Vulcan model 3-550 oven (see Example 39) tosimulate conditions typically encountered in “dry heat” sterilizationprocedures. The following table summarizes these experiments:Temperature (° C.) Time (h) Observations 130 3 No color change 130 6Very slight yellowing 130 15  Very slight yellowing 150 4 Very slightyellowing 170 1 Very slight yellowing 170   3.5 Pale yellow at surface,white interior

[0263] It was assumed that temperature equilibration between the samplesand the oven was rapidly attained due to the significant porosity andlow thermal mass of the materials. Clearly, there was no significantdegradation of the gelatin under these heat treatment regimens.Furthermore, a subjective assessment of the strength of these dry heattreated specimens showed no apparent changes.

Example 50 Template Residues

[0264] A bolck of damp (as removed from the packaging) O-Cel-O™ brandcellulose sponge with a weight of 7.374 g, setting on a platinum plate,was placed into a Vulcan model 3-550 oven preheated to 500° C. and heldat that temperature for 1 hour. At the conclusion of the burnout cycle,0.073 g of fluffy gray ash was collected representing approximately 0.99wt % of the original cellulose sponge mass.

[0265] A block of damp (as removed from the packaging) Marquis™ brandcellulose sponge with a weight of 31.089 g, setting on a platinum plate,was placed into a Vulcan model 3-550 oven preheated to 500° C. and heldat that temperature for 1 hour. At the conclusion of the burnout cycle,1.84 g of fluffy gray ash was collected representing approximately 5.9wt % of the original cellulose sponge mass. An XRD pattern obtained fromthis ash residue (FIG. 23) indicated the simultaneous presence ofmagnesium oxide, MgO (major) (PDF 45-0946) and sodium chloride,NaCl(minor) (PDF 05-0628) both phases resulting from the correspondingchloride salts used in the manufacturing process of the cellulosesponge. The presence of these two salts, in particular the MgO, mayaccount for the “incomplete” burnout of the inorganic sponge material at500 to 800° C. as noted in Examples 39, 41-44, 47, and 48.

[0266] Another block of the Marquis™ brand cellulose sponge wasextensively washed in deionized water by repetitive kneading andmultiple water exchanges. This thoroughly washed sponge was allowed todry in air at room temperature for two days, after which it was cut intotwo blocks. The density of the washed and air-dried sponge comprisingeach of these two blocks was calculated to be approximately 1.03g/inch³. Each of these blocks of washed and air dried sponge was burnedout according to the aforementioned procedure. An insignificant amountof ash was collected from each sample, indicating the efficacy of thewashing procedure for removing salt contaminants.

Example 51 Alternative Templates

[0267] A reactant solution was prepared as described in Example 39. Avariety of shapes, including disks, squares, and triangles, were cutfrom a sheet of 3/32 inch thick “Normandy compressed sponge” (Spontex,Inc., P.O. Box 561, Santa Fe Pike, Columbia, Tenn. 38402) using eitherscissors or hollow punches. This compressed cellulose sponge ismanufactured to have a smaller median pore size and a narrower pore sizedistribution than either of the commercially available household sponges(O-Cel-O™ or Marquis™) used in Examples 39-50. This compressed spongealso has low ash levels (<0.1 wt % when burned out according to theprocedure mentioned in Example 50) indicating that it is washedessentially free of salts during fabrication. The sponge is compressedinto a sheet which, upon rewetting, expands to restore the originalcellular sponge structure which, in the case of this particular example,is approximately 1 inch thick. Imbibation of water into the compressedsponge to saturation levels results in a weight increase ofapproximately 28 times over the dry sponge weight. The cut pieces ofcompressed sponge were fully imbibed with the reactant solution afterwhich they swelled to form cylinders, cubes, and wedges. These solutionsaturated sponge articles, setting on Pt plates, were placed into aVulcan model 3-550 oven preheated to 500° C. and held at thattemperature for 1 hour. After cooling, the inorganic sponge pieces werecarefully removed from the considerable amount of crusty white solidresulting from the exudate material. All samples had been converted toan inorganic replica of the original organic sponge structures. Thevestigial structures represented positive versions of the originalsponge structures with faithful replication of the cellular elements andporosity. The vestigial masses were fragile with very low apparentdensity, but they were robust enough to be handled as coherent blocks ofhighly porous solid once they were removed from the exudate material.The inorganic sponge material was mottled gray, suggesting the presenceof some residual carbon in the structure. After refiring the samples at800° C. (Vulcan furnace) for 15 minutes, the final inorganic spongesamples were completely white. The integrity of the various samples madefrom the controlled porosity cellulose sponge was improved overcorresponding samples prepared from the commercial cellulose spongematerials.

[0268]FIG. 24 is a SEM of the Normandy compressed sponge expanded indeionized water and prepared for microscopy as described in Example 39.

Example 52 Modified Templates

[0269] Pieces of the inorganic sponge material from Example 51 wereimmersed in a gelatin solution prepared as described in Example 46except that 7.1 g of Knox gelatin was dissolved in 200 g deionized waterrather than 100 g of deionized water. The inorganic sponge materialreadily imbibed the warm gelatin solution and, after several minutes,the largely intact pieces of inorganic sponge material were carefullyremoved from the solution and allowed to cool and dry at roomtemperature. Significant additional strength and improved handlingproperties were noted in the gelatin-treated inorganic sponge materialafter the gelatin was allowed to thoroughly dry for several days. Thematerial exhibited considerable improvement in compression strength anda dramatically reduced tendency to shed particulate debris when cut witha knife or fine-toothed saw.

[0270] Several pieces of gelatin treated sponge which had been drying inair for >1 week were subjected to a burnout of the organic material at800° C. (Vulcan furnace) for 30 minutes. The snow white inorganic spongesamples were weighed after firing and it was determined that the levelof gelatin in the treated samples was 13.8+/−1.0 wt % (with respect tothe inorganic sponge material).

[0271]FIG. 25 is a SEM of the air-dried gelatin treated inorganic spongewhich was prepared as described above. A comparison of this SEM withthat of the initial cellulose sponge material (FIG. 24) shows howfaithfully the sponge micro- and macrostructure has been replicated inthe polymer coated inorganic sponge material.

Example 53 Rewetting

[0272] Several pieces of air-dried gelatin-treated inorganic spongematerial from Example 46 were placed in deionized water to assess therewetting/rehydration behavior. Initially, the pieces floated at thewater surface but, after approximately 2 hours, the sponge pieces beganto float lower in the water indicating liquid uptake. After 24 hours,the samples were still floating, but >50% of the sponge volume was belowthe liquid surface. After 48 hours, the inorganic sponge samples werecompletely submerged suggesting complete rehydration of the gelatin andcomplete water ingress into the structure via interconnected porosity.

Example 54 Shaped Calcium Phosphates

[0273] Several pieces of the inorganic sponge material from Example 39were immersed in a 50 wt % solution of disodium glycerophosphate hydrateprepared by dissolving 10.0 g C₃H₇O₆PNa₂ (Sigmna Chemical Co. reagentG-6501, CAS # 154804-51-0), equivalent to 65.25 wt % as “Na₂PO₄”, in10.0 g deionized water. The inorganic sponge material readily imbibedthe disodium glycerophosphate solution and, after several minutes, thelargely intact pieces of saturated inorganic sponge material werecarefully removed from the solution. The wetted pieces, setting on a Ptplate, were placed in a Vulcan model 3-550 oven preheated to 150° C.Immediately, a temperature ramp to 850° C. was begun (duration of 50minutes) followed by a 60 minute hold at 850° C. After cooling to roomtemperature, the surface of the treated inorganic sponge material had aglassy appearance, and significant additional strength and improvedhandling properties were noted. Upon examination of the pieces with aLeica zoom stereo microscope, the presence of a glassy surface wasconfirmed and rounding of the features was evident indicating that somelevel of sintering had occurred. Considerable shrinkage of the pieceswas also noted.

[0274] An XRD pattern was obtained from a packed powder sample preparedas described in Example 39. Peak analysis indicated the solid toconsist, in part, of Buchwaldite, sodium calcium phosphate, NaCaPO₄ (PDF29-1193 and 29-1194).

Example 55 Discoid Bodies

[0275] A reactant solution was prepared as described in Example 39.Disks were cut from a sheet of {fraction (3/32)} inch thick Normandycompressed sponge using a ⅜ inch diameter hollow punch and a model no.3393 Carver hydraulic press (Carver Inc., 1569 Morris St., P.O. Box 544,Wabash, Ind. 46992) to ensure uniform sizing. The disks were distendedby immersion in deionized water and the resulting sponge cylinders, eachapproximately ⅜ inch diameter by 1 inch length, were then blotted onpaper towel to remove as much excess water as possible. The damp spongecylinders were then imbibed with approximately seven times their weightof the reactant liquid. Nine of the solution imbibed pieces were placedhorizontally and spaced uniformly in a 100×20 mm Pyrex petri dish. Twopetri dishes, containing a total of 18 imbibed sponge cylinders, werepositioned in the center of the cavity of a microwave oven (Hotpointmodel no. RE963-001, Louisville, Ky. 40225) and the samples wereirradiated at full power for a total of two minutes. After 30 seconds ofexposure, the microwave oven cavity was full of NOx(g) and the reactantliquid which had exuded from the sponge cylinders had reacted/dehydratedto form a crusty white deposit in the petri dishes. The oven was openedto vent the cavity, then full power irradiation was resumed. Afteranother 30 seconds of exposure, the oven cavity was again full ofNO_(x)(g) and steam. After venting the cavity once more, full powerexposure was resumed for an additional 60 seconds, after which the fullydry sponge cylinders were removed. The sponge cylinders retained theorange color of the original cellulose material and a considerablefraction of the pores were filled with white solid. The pieces were veryrobust at this point, there was little or no warpage or slumping, andthey could be handled and even abraded to shape the pieces and to removeasperities and any adherent solid resulting from the exuded liquid. Thedried, solid-filled cylindrical sponge pieces were arrayed in arectangular alumina crucible (2½″W×6″ L×½″ D) and placed in a furnacepreheated to 500° C. The furnace temperature was ramped at 40° C./minuteto 800° C. and held at 800° C. for 45 minutes. The resultant cylindricalwhite porous inorganic sponge samples were robust and exhibitedstrengths qualitatively similar to those attained from the fully driedgelatin-treated samples prepared as described in Example 52.

[0276] An XRD pattern was obtained from a packed powder sample preparedfrom the material fired at 800° C. Peak analysis indicated the solid toconsist solely of whitlockite, beta-Ca₃(PO₄)₂ (PDF 09-0169).

Example 56 Implantation of Calcium Phosphate Shaped Plug into CanineMetaphyseal Bone

[0277] The porous calcium phosphate scaffolds, prepared as described inExample 55, are instantly wetted by water, aqueous solutions, alcohols,and other hydrophilic liquids in distinct contrast to the gradualrewetting of the gelatin-treated scaffold structure (Example 53). Bloodreadily wicks into the porous calcium phosphate bodies without obviousdetrimental effects. It is believed that cells, e.g., fibroblasts,mesenchymal, stromal, marrow, and stem cells, as well as protein-richplasma and combinations of the aforementioned cells carl also be imbibedinto the porous structures.

[0278] Highly porous calcium phosphate cylindrical plugs were preparedas described in Example 55 starting with 10 mm discs punched fromNormandy compressed sponge. The cylindrical porous bodies were dry heatsterilized in Dualpeel™ self seal pouches (distributed by AllegianceHealthcare Corp., McGaw Park, Ill. 60085) at 125° C. for 8 hours.

[0279] An animal experiment was initiated at Michigan State University,whereby a 10.3 mm×25 mm defect was drilled into the right shoulder(greater tubercle) of mongrel dogs. The site was cleaned of bonefragments and the site filled with blood (and marrow cells) as the sitewas centered in metaphyseal bone. The scaffold implants were removedfrom their sterile pouch and inserted into the defect site. Initialpenetration to half of the 25 mm depth was easily achieved with littleresistance. Slight pushing was required to insert the remainder of theimplant into the site, such that the top of the scaffold was flush withthe cortical bone surface. During insertion, blood could be seen readilywicking up the porous scaffold. After complete insertion of the implant,blood could be seen flowing throughout and around the scaffold. Theimplant intergrity was maintained with no fragmentation or breakage. Thecompatibility with blood and marrow was evident. The surgical site wasthen closed.

[0280]FIG. 26 shows the cylindrical implant with initial wicking ofblood. FIG. 27 depicts implantation of the cylinder into the caninebone.

Example 57 Porous Shaped Bodies of Hydroxyapatite

[0281] The mineral phase of human bone consists primarily ofcompositionally modified, poorly crystalline hydroxyapatite,Ca₅(PO₄)₃(OH). The hydroxyapatite crystallographic structure ispartially substituted by carbonate anions (7.4 wt. %) as well as bymetal cations present at fractional wt. % levels. Analysis of human bone[R. Z. LeGeros, “Calcium Phosphates in Oral Biology and Medicine,”Monographs in Oral Science, Vol. 15 (H. M. Myers, Ed.), p 110, KargerPress (1991)] indicates, for example, that the principal trace cationicconstituents are as follows: Na⁺ (0.9 wt. %), Mg²⁺ (0.72 wt. %), andZn²⁺ (trace, assumed as 0.05 wt. %). Heretofore, it has been difficult,if not impossible, to synthesize hydroxyapatite mineral doped withcations to the appropriate levels so as to approximate bone mineral. Aunique capability and distinct advantage of the RPR method is the facilemanner in which precursor solutions containing mixed metal ions can beprepared and converted into solid phases via the redox precipitationreaction and subsequent thermal processing.

[0282] A reactant solution was prepared by combining 7.88 g 50 wt. %hypophosphorous acid, H₃PO₂, with 5.00 g deionized water in a 250 mlPyrex beaker. To this solution was added 22.51 g calcium nitratetetrahydrate salt, Ca(NO₃)₂.4H₂O; plus 0.33 g sodium nitrate salt, NaNO₃(Fisher Certified ACS reagent #S343-500, CAS #7631-99-4), equivalent to27.05 wt. % Na; plus 0.74 g magnesium nitrate hexahydrate salt,Mg(NO₃)₂.6H₂O (Alfa/Aesar reagent #11564, CAS 13446-18-9), equivalent to9.48 wt. % Mg; plus 0.046 g Zn(NO₃)₂.6H₂O (ACS reagent, Aldrich ChemicalCo., Inc. #22,873-7, CAS 10196-18-6), equivalent to 21.97 wt. % Zn.Endothermic dissolution of the salts proceeded with stirring and gradualwarming on a laboratory hot plate to approximately 20° C., eventuallyforming a homogeneous solution with a water-like viscosity despite thehigh salt concentration. The equivalent solids level (as cationsubstituted hydroxyapatite) was 27.39 wt. % and the target solidcomposition was 38.19 wt. % Ca, 0.90 wt. % Na, 0.70 wt. % Mg, 0.10 wt. %Zn, 56.72 wt. % PO₄, and 3.39 wt. % OH.

[0283] Eighteen ⅜-inch diameter×1-inch length cylinders of Normandysponge were imbibed with this reactant liquid to approximately seventimes their initial weight and microwave processed as described inExample 55. The dried, solid-filled cylindrical sponge pieces were thenfired according to the procedure described in Example 55. The resultantcylindrical white porous inorganic scaffold samples were robust andsubjectively equivalent in strength to the articles produced in Example55.

[0284] An XRD pattern, FIG. 28, was obtained, as described in Example39, from a packed powder sample of the material fired at 800° C.Analysis of both peak position and relative intensities over the angularrange from 10 to 60 degrees (2-theta) indicated the solid to consist ofhydroxyapatite (PDF 09-0432). Additionally, four unassigned peaks at29.9, 31.3, 34.7, and 47.4 degrees (2-theta) were observed in thissample. These are, presumably, due to the cationic substitutions leadingto a distorted hydroxyapatite lattice structure.

[0285] The inorganic porous material prepared in Examples 39 through 57,deinved from the precursor aqueous solutions involving the minerals ormaterials described in the preceding Examples 1 though 38, can beutilized in a variety of applications. These applications include, butare not limited to: bone or teeth replacement, filters, catalyticconverters, catalytic substrates, bioseparations media, pharmaceuticalexcipients, gas scrubber media, piezoelectric ceramics, pharmaceuticaldrug delivery systems, or aerators. As the examples illustrate, thecomposition can be easily tailored to accommodate the particular end usewithout the concerns of extensive material preparation such aspurification or particle size treatment. Further, the porous inorganicmaterial can be formed into a variety of practical shapes withoutelaborate tools or machining.

Example 58 Composite Members for Reconstructive Use

[0286] A composite structure in accordance with this invention can beformed from an RPR material and from polymerizable material. A shapedstructure is molded from an RPR material, especially one which givesrise to calcium phosphate. Any of the foregoing methods for preparingshaped bodies of RPR can be used in this context. Thus, for example, anRPR calcium phosphate is molded in the shape of an elongated rectangularprism. The shape is preferably purged of any cellulosic or othermaterial used in its formation and is rinsed of acidic residues andrendered sterile.

[0287] The shaped calcium phosphate is then coated with hardenablematerial such as any of the polymerizable systems described heretofore.It is preferred that the polymerizable material be an acrylic systemhaving inorganic fillers, especially where such fillers comprise atleast a portion of Combeite to render the same bioactive. The hardenablematerial is then hardened either through thermal or photochemicalmechanisms or otherwise.

[0288] The resulting composite structure has a core of RPR materialsurrounded by a layer of hard polymer, preferably a polymer exhibitingbioactivity. As will be apparent, this structure mimics e mammalianbone, having a trabecular internal structure surrounded by a cancellous,hard exterior. Such structures may be elaborated in a very wide array ofshapes for use in orthopaedic and other surgical restorations andreconstructions. On particular use is in the preparation of vertebralappliances such a cages, rings spacers and spinal devices of many kinds.An additional use is in the preparation of materials for structural bonerepair and the like. Thus, it can be seen that the RPR material whichforms the overall shape of the structure can be molded or otherwiseformed into a wide variety of shapes and, indeed, may be formed “toorder” in an operating room. Thus, RPR materials can be milled or carvedfrom a preformed block to precisely match a prepared location forsurgical reconstruction. The shaped RPR material may then be coated withpolymerizable material in any number of ways and the polymer cured,especially via actinic light. The coating with polymerizable materialmay be accomplished via dipping, spraying, painting, extrusion,sculpting, or, in short, in any convenient way amenable to thepolymerizable material being used.

[0289] While the polymerizable material can be thermally cured, such aswhen two-paste systems are employed, actinic light curing systems arepreferred. Such actinic light curing is widely practiced in dentalrestoration and its techniques are well-known and can be easily modifiedto the practice of this invention. The preparation of the restorationcan be accomplished in a matter of minutes, minimizing operative time.The restoration comprising the composite structures of this invention isapplied to a prepared site and preferably adhered therein. For thispurpose, polymerizable adhesives in the form of pastes, putties orliquids are employed, especially those formed from acrylic systems. Mostpreferred are acrylic cements and putties including fillers havingbioactive fillers, especially Combeite. In accordance with somepreferred embodiments, cement access orifices are provided in thecomposite shaped bodies of the invention. Such holes permit goodpenetration of adhesive or cements and may offer superior performance.

[0290] It will be appreciated that the polymerizable material coatedupon the RPR material may be all or partially polymerized in situ toeither serve the adhesive function or to assist therein. It can beconvenient to apply two or more layers of polymerizable material to theRPR structure for diverse purposes. Indeed, several differentpolymerizable systems may be employed. Thus, one layer or coating may beapplied for strength, another for biocompatibility and a third foradhesive purposes. Other functions or combinations may be employed.

[0291] The composite structures of this invention can mimic natural bonestructure. It is believed that the presence of an open trabecularstructure provided by the RPR material together with the hard, strongstructure mimicking cancellous bone as can be provided by acrylicpolymers gives rise to superior results in use. Thus, the restorativecomposite structures are immediately weight bearing, while theirtrabecular structure provides less mass and confers some resilience tothe restoration. This composite structure provides restorations whichare easily accepted by natural bone and which does not overly stressnatural structures.

[0292] It will be appreciated that the methods for accomplishing theparticular steps described above are well known to persons of ordinaryskill in the art in view of the present specification, of U.S. Pat. Nos.5,681,872 and 5,914,356 and the specifications of U.S. Ser. Nos. 784,439filed Jan. 16, 1997; 011,219 filed Dec. 12, 1997; and 253,556 filed Feb.19, 1999; incorporated herein by reference.

Example 59 Reinforced Composite Members

[0293] A composite member for reconstructive use can be prepared inaccordance with the previous example, but with the inclusion ofreinforcements. Thus, an RPR shape is molded, extruded, or otherwiseformed surrounding or substantially surrounding one or more rods orother reinforcements. The resulting structure is, itself, a compositestructure in accordance with the invention. It is preferred, however, tofurther elaborate upon the structure by applying to it polymerizablematerial for subsequent curing and use. It will be understood thatreinforcement may take the form of metallic, ceramic, glass, polymericor other structures within or upon one of the portions of the compositestructures of this invention and that such reinforcement may be includedfor purposes of strength, durability, biostimulation, biocompatibility,drug delivery, biopharmaceutical delivery or many other fuinctions.

Example 60 Complex Composite Members

[0294] A shape is molded from acrylic polymer filled with silanatedmicrofine silica in accordance with conventional techniques. The shapeis selected to closely mimic a lachrymal bone in an adult human. Themolded shape is coated with calcium phosphate RPR precursor material,including a cellulosic material to form a viscous putty-fluid. The RPRreaction is caused to occur and the resulting RPR material is heated,washed and otherwise treated as the practitioner may desire. Theresulting structure comprises the acrylic shape coated with RPR materia,the whole taking the overall shape of the original acrylic body. Aplurality of holes are drilled in the body (or were present in theoriginal molded form). A further polymer-forming mixture is then appliedto the shaped body to coat all or a portion of it. The same ispolymerized yielding a “three layer sandwich” arrangement of polymercore, RPR layer and polymer top coating. The materials are selected suchthat the overall structure is strong, but somewhat flexible. Uponapplication of crushing force, the structure crushes rather thanshatters. Accordingly, when used in facial reconstruction, the bonereplacement thus formed will crush and deform, rather than shatter intopotentially lethal shards.

Example 61 Composite Catalytic Structures

[0295] Helices, tori, Raschig rings, microtubes and other structures foruse in packing chemical processing vessels, columns and the like can beformed in accordance with the invention. Thus, metallic shapes areformed in the desired configuration and coated with RPR material. SinceRPR materials can be formed in a very wide variety of chemical forms andstructures, extraordinary flexibility in the provision of suchstructures can be accomplished. Thus, structures having platinum,nickel, nickel alloys, palladium, copper, iron and many other chemicalmoieties may be exposed to chemical processes in a solid, easilyfilterable or, indeed, stationary form. Diverse catalytic and separatoryfunctions may be accomplished with such structures.

[0296] The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims rather thanto the foregoing specifications, as indicating the scope of theinvention.

What is claimed is:
 1. A shaped body comprising: a first segmentcomprising a polymerizable matrix and an inorganic filler; and incontact with at least a portion of the first segment, a second segmentcomprising an inorganic material having substantially uniform macro-,meso- and microporosity together with a pore volume of at least about30%.
 2. The shaped body of claim lwherein the inorganic materialcomprises calcium phosphate.
 3. The shaped body of claim 1 wherein thepore volume of the inorganic material is at least about 50%.
 4. Theshaped body of claim 1 wherein the pore volume of the inorgaric materialis at least about 70%.
 5. The shaped body of claim 1 wherein the porevolume of the inorganic material is at least about 90%.
 6. A compositebody having at least two portions: a first portion comprising theoxidation-reaction product of a blend comprising at least one metalcation; at least one oxidizing agent; and at least one precursor anionoxidizable by said oxidizing agent to form an oxoanion; the secondportion being imbibed into the first portion.
 7. The composite body ofclaim 6 wherein the second portion is polymerized.
 8. The composite bodyof claim 6 wherein the second portion is selected from the groupconsisting of polycaprolactones, polyglycolic acid, poly-L-lactic acid,polysulfones, polyolefins, polyvinyl alcohol, polyalkenoics, polyacrylicacids, and polyesters.
 9. A composite body for drug delivery comprising:a first portion comprising the oxidation-reaction product of a blendcomprising at least one metal cation; at least one oxidizing agent; andat least one precursor anion oxidizable by said oxidizing agent to forman oxoanion; a second, resorbable portion imbibed into the firstportion; and a medicament.
 10. The composite shaped body of claim 9wherein the medicament is absorbed into the solid composite body. 11.The composite shaped body of claim 9 wherein the medicament is a growthhormone, antibiotic material, proteins, cell signaling material,steroids, analgesics, or fertility drugs.
 12. A shaped body comprising:a first portion comprised of an inorganic material having substantiallyuniform macro-, meso- and microporosity together with a pore volume ofat least about 30%; and a second portion that contacts at least aportion of the first portion, wherein the second portion is comprised ofa powder.
 13. The shaped body of claim 12 wherein the powder is L-lacticacid.
 14. A shaped body comprising: a first portion comprised of aninorganic material having substantially uniform macro-, meso- andmicroporosity together with a pore volume of at least about 30%; and asecond portion that contacts at least a portion of the first portion,wherein the first portion is a hollow sleeve.
 15. The shaped body ofclaim 14 wherein the second portion is a graft material.
 16. The shapedbody of claim 14 wherein the second portion is a hardenable fluidmaterial.
 17. The shaped body of claim 16 wherein the fluid material isa liquid, paste, putty or gel.
 18. The shaped body of claim 16 whereinthe fluid material is polymerizable.
 19. The shaped body of claim 16wherein the fluid material is acrylic.
 20. The shaped body of claim 14wherein the outer surface of the hollow sleeve includes a plurality oforifices.